Inflammopharmacol
DOI 10.1007/s10787-010-0073-1
REVIEW
Lysyl oxidase: a potential target for cancer therapy
Siddikuzzaman • V. M. Berlin Grace •
C. Guruvayoorappan
Received: 3 September 2010 / Accepted: 2 November 2010
Ó Springer Basel AG 2010
Abstract Lysyl oxidases (LysOX; EC 1.4.3.13, protein-
lysine 6-oxidases) are extracellular copper enzymes that
catalyze the cross-linking of collagens or elastin in the
extracellular matrix (ECM), thereby regulating the tensile
strength of tissues. Recent implication of LysOX in cancer,
wound healing, cell motility, chemotaxis, and differentia-
tion reflects its remarkable functional diversity and also in
the central nervous system pathologies. However, recent
reports also demonstrated novel roles for LysOX, including
the ability to regulate gene transcription, motility/migra-
tion, and cell adhesion. These diverse functions have led
researchers to hypothesize that LysOX may have multiple
roles affecting both extra- and intracellular cell function(s).
Both down and up-regulation of LysOX in tumor tissues
and cancer cell lines have been described, suggesting a
dual role for LysOX as a tumor suppressor, as well as a
metastasis promoter gene. In this review we explain in
detail the role of lysyl oxidase in tumor progression and
metastasis.
Keywords Lysyl oxidase
Copper
Extra
cellular matrix
Cancer
Tumor suppressor

Metastasis promoter
Introduction
The extracellular matrix (ECM) is essential for providing
mechanical and physiological properties for various tissues,
and it also provides attachment sites for the anchoring of
Siddikuzzaman
V. M. B. Grace
C. Guruvayoorappan (&)
Department of Biotechnology, Karunya University, Karunya
Nagar, Coimbatore 641114, Tamil Nadu, India
e-mail: gurukarunya@gmail.com
Inflammopharmacology
cells and support for their migration in tissues. It also sup-
ports physical structure formation of tissues during
development and tissue maintenance, determines cell–
matrix and cell–cell interactions, and provides a structural
and signaling environment that is necessary for cell
migration, proliferation, and differentiation. The ECM
plays a pivotal role in regulation of cellular functions during
embryonic development, tissue repair, inflammation, tumor
invasion, and metastasis (Hynes 2002; Juliano 2002). The
composition of the ECM is unique for each organ. It con-
sists of numerous compounds including insoluble fibers,
microfibrils, soluble proteins, and glycoproteins.
The lysine residues of the ECM molecules, such as of
collagen and elastin go through oxidative deamination by
the extracellular enzyme lysyl oxidase (LysOX), a copper
dependent amine oxidase, which forms reactive aldehyde
of its substrates (Kagan 1994; Gibson et al. 1996). The
newly formed aldehyde residues then interact spontane-
ously to form covalent cross-linkages leading to insoluble
extracellular protein matrices in most tissues and organs
(Nagan and Kagan 1994; Smith-Mungo and Kagan 1998).
The essential function of LysOX in the ECM and LysOX
cellular distribution in the skin, lung, and the cardiovas-
cular systems have been well characterized. Recently, in
addition to its ECM cross-linking activity several studies
reported novel roles for LysOX in diverse tumor types and
a major role in invasive breast cancer cells and tumors.
Although the ECM maturation activity of LysOX has
long been thought to be its sole function, more recent
evidence implicates the involvement of LysOX in many
critical biological functions other than collagen or elastin
cross-linking. LysOX has been shown to induce motility
and migration in monocytes, vascular smooth muscle cells,
and fibroblasts (Nelson et al. 1988; Lazarus et al. 1994; Li
et al. 2000). In addition, LysOX expression and activity
123

have been observed in the cytoplasm and nucleus (Waka-
saki and Ooshima 1990; Li et al. 1997; Nellaiappan et al.
2000; Kagan and Li 2003; Lucero and Kagan 2006; Jansen
and Csiszar 2007) and implicated in cell signaling and
transcriptional gene regulation, as evidenced by utilization
of histone H1 and H2 as substrates (Kagan et al. 1983;
Giampuzzi et al. 2003a), altered chromatin condensation
(Mello et al. 1995), activation of the collagen III a1 pro-
moter through LysOX induced binding of Ku antigen
(Giampuzzi et al. 2000), inactivation of the transcription
factor NF-jB (Jeay et al. 2003), and regulation of cell
adhesion through increased b-catenin and cyclin D1
expression (Giampuzzi et al. 2005). Even more recent are
the findings that LysOX protein domains, other than the
catalytic domain, can bind to proteins, as with binding to
fibronectin (Fogelgren et al. 2005) and placental lactogen
(Polgar et al. 2007) and that the cleaved 18 kDa LysOX
propeptide (LysOX-PP) is also capable of regulating bio-
logical functions (Palamakumbura et al. 2004). Since
LysOX protein structure and function are so complex and
involve such vital biological processes as cell movement,
signal transduction, and gene regulation, it is evident that
aberrant regulation of LysOX would lead to tumorigenesis
and tumor progression. Indeed, loss of LysOX expression
and activity in a number of cancers and oncogene-trans-
formed cell models has implicated LysOX as a tumor
suppressor gene. Likewise, LysOX expression and activity
in a number of cancers has also been observed and has
implicated LysOX as a metastasis promoting gene—cre-
ating a conundrum within the LysOX research field with
regard to LysOX biological function(s) in cancer. This
review will summarize the role of LysOX in tumorigenesis
and tumor progression with an emphasis on cancer meta-
static progression.
The lysyl oxidase protein family
Lysyl oxidase (LysOX; protein-6-oxidase [EC 1.4.3.13]) is
the key enzyme that controls collagen and elastin matura-
tion (Pinnell and Martin 1968; Smith-Mungo and Kagan
1998). LysOX is the copper- and quinone-containing amine
oxidase that catalyzes the oxidative deamination of peptidyl
lysine in elastin and collagen to a-aminoadipic-d-semial-
dehyde, the first step in formation of the cross-links that
stabilize these structural proteins (Faina and Frederick
2010).The consequent aldehydes lead to a spontaneous
condensation forming inter- and intrachain cross-links. This
posttranslational modification of ECM molecules plays a
very important role in collagen and elastin structural aspects
and possibly in triggering still-unknown signal transduction
pathways. Several reports have suggested a clear associa-
tion between organ fibrosis and increased LysOX activity
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Siddikuzzaman et al.
(Chanoki et al. 1995; Jourdan-Le Saux et al. 1994; Sommer
et al. 1993). The most intriguing aspect regarding LysOX
activity relates to its putative cell phenotype control and
tumor suppressor activity. LysOX was identified as a ‘‘ras
recision gene’’ (rrg), and levels of LysOX were found to be
decreased in cells transformed by ras or ras-dependent
oncogenes (Contente et al. 1990; Kenyon et al. 1991;
Krzyzosiak et al. 1992). Furthermore, Friedman and
coworkers showed that ras-transfected NIH 3T3 cells
induced to revert by beta or gamma interferon would return
to their transformed phenotype upon transfection with an
antisense LysOX vector, and retransformation did not affect
p21ras levels (Contente et al. 1990; Kenyon et al. 1991). In
many naturally occurring and oncogene-induced tumors,
LysOX is down regulated, and LysOX was induced con-
comitantly with reversion (Contente et al. 1990; Kenyon
et al. 1991; Krzyzosiak et al. 1992; Giampuzzi et al. 2001;
Hajnal et al. 1993; Hämäläinen et al. 1995).
However, this oxidative activity does not display high
specificity because LysOX can also oxidize additional
lysine-rich proteins such as histone-H1, as well as various
lysine-rich synthetic peptides (Kagan et al. 1983; Ohkawa
et al. 2001). It was observed that LysOX can be translo-
cated into cell nuclei and that it can regulate, by an as yet
poorly understood mechanism, the expression of collagen-
3A1, indicating that LysOXs may have additional functions
(Nellaiappan et al. 2000; Giampuzzi et al. 2000). LysOX is
synthesized as an inactive proenzyme that is activated by
the products of the BMP-1 gene (Panchenko et al. 1996).
Recently, several additional LysOX family members were
identified. These new family members are characterized by
the presence of a conserved LysOX-like domain containing
conserved copper binding and catalytic domains at their
COOH termini. These new LysOXL genes include Lys-
OXL (Kenyon et al. 1993; Kim et al. 1995), LysOXR-1 or
LysOXL2 (Saito et al. 1997), LysOXR-2 or LysOXL3
(Huang et al. 2001), and LysOXC or LysOXL4 (Maki et al.
2001). LysOXR-1, LysOXR-2, and LysOXC differ with
respect to LysOX and LysOXL in that they possess a much
longer NH2-terminal domain, suggesting that they consti-
tute a distinct subclass of LysOXs and that their functions
may differ fundamentally from those of LysOXL and
LysOX (Csiszar 2001). LysOXR-1 was initially identified
as a gene the expression of which is up-regulated in
senescent fibroblasts and in adherent tumor-derived cells
(Saito et al. 1997). It was also found to be highly expressed
in reproductive tissues (Jourdan-Le Saux et al. 1999). It
was demonstrated that LysOXL is also processed into its
active form by bone morphogenetic protein-1, raising the
possibility that the proteins encoded by the other family
members may also be activated by proteolytic digestion
after secretion. The transition from a localized tumor to an
invasive and metastatic tumor represents a landmark in the
Lysyl oxidase: a potential target for cancer therapy
development of malignant disease because it is usually
associated with a markedly worse prognosis. The under-
standing of the processes that govern this transition is
therefore, of prime importance. It was recently observed
that, in breast cancer the transition from a localized to an
invasive/metastatic tumor is associated in many cases with
the formation of fibrotic foci and desmoplasia (the presence
of unusually dense collagenous stroma) within the primary
tumor (Colpaert et al. 2001; Hasebe et al. 2000). There are
also some indications that a similar correlation may exist in
other types of cancers such as in colon cancer and in
pancreatic cancer (Nishimura et al. 1998; Ellenrieder et al.
2000). These observations represent apparent paradoxes at
first glance because invasiveness has long been associated
with the destruction of ECM by ECM-degrading enzymes
like metalloproteases (Stamenkovic 2000; Duffy et al.
2000) and heparanase (Vlodavsky and Friedmann 2001).
However, it is possible that the deposition of excess ECM
may stimulate, in turn, expression of matrix-degrading
enzymes that will contribute under certain circumstances to
tumor invasion. In fact, there is some evidence that an
increase in ECM deposition can, indeed, influence the
production of ECM-degrading enzymes (Schuppan et al.
2001; Sawada et al. 2001). Two LysOX family members,
LysOX and LysOXL, were found to be expressed in areas
of fibrogenesis in noninvasive in situ ductal breast carci-
nomas (Decitre et al. 1998). However, it was reported that
metastatic breast cancer cell lines express LysOX, Lys-
OXL, and LysOXR-1, whereas nonmetastatic breast
cancer-derived cell lines, such as MCF-7 cells, do not, and
that LysOX-expressing MCF-7 cells display increased
invasiveness in in vitro invasiveness assays (Kirschmann
et al. 2002). It also reported that LysOXR-1 expression in
nonmetastatic MCF-7 cells induces massive deposition of
dense collagen fibers and the formation of numerous
fibrotic foci in tumors that develop after the implantation of
these cells in nude mice. These changes were accompanied
by an increase in the invasiveness of the MCF-7 cells,
although the LysOXR-1-expressing cells were still estro-
gen dependent.
Physical and biological properties of LysOX
LysOX is a copper-dependent amine oxidase that initiates
the covalent cross-linking of collagens and elastin in
extracellular matrices (Smith-Mungo and Kagan 1998;
Csiszar 2001). It is secreted as a Mr 50,000 glycosylated
proenzyme, which is proteolytically processed by procol-
lagen C proteinase (bone morphogenic protein-1) into a
mature, biologically active Mr 32,000 form (Smith-Mungo
and Kagan 1998; Csiszar 2001). The formation of collagen/
elastin cross-links by LysOX leads to an increase in tensile
strength and structural integrity and is essential for normal
connective tissue function, embryonic development, and
wound healing (Smith-Mungo and Kagan 1998; Casey and
MacDonald 1997). Consequently, aberrant LysOX
expression or enzymatic activity leads to disease. Decrea-
ses in LysOX expression or activity have been associated
with such heritable connective tissue disorders as Ehler-
Danlos syndrome, cutis laxa, and Menkes’ syndrome
(Kuivaniemi et al. 1985; Khakoo et al. 1997; Yeowell et al.
1994; Royce et al. 1980; Pinnell 1982). Increases in LysOX
expression contribute to the development of fibrotic dis-
eases such as arteriosclerosis, scleroderma, and liver
cirrhosis, diseases that involve connective tissue remodel-
ing (Ooshima and Midorikawa 1977; Kagan et al. 1981;
Chanoki et al. 1995; Kagan 1994). Upregulation of lysyl
oxidase expression by uric acid leads to increases fibro-
nectin synthesis in rat renal tubular epithelial cells (Zhou
et al. 2010).
Although the ECM maturation activity of LysOX has
long been thought to be its sole function, more recent
evidence implicates the involvement of LysOX in many
important biological functions other than collagen/elastin
cross-linking. LysOX has been shown to induce motility
and migration in monocytes, vascular smooth muscle cells,
and fibroblasts (Lazarus et al. 1994; Li et al. 2000; Nelson
et al. 1988). In addition, LysOX may play a role in cell
growth/differentiation as its expression is up-regulated by a
number of growth factors and steroids (Lazarus et al. 1994;
Li et al. 2000; Nelson et al. 1988; Sanada et al. 1978).
Moreover, a role for LysOX in transcriptional gene regu-
lation and cellular transformation has also been implicated
as evidenced by localization of LysOX protein and enzy-
matic activity to cell nuclei (Li et al. 1997), potential
utilization of histone H1 as a substrate (Kagan et al. 1983),
activation of the collagen III a1 promoter (Giampuzzi et al.
2000), and a putative tumor suppressor in nontumorigenic
revertants of ras-transformed fibroblasts (Smith-Mungo
and Kagan 1998).
LysOX was purified from a variety of tissues and spe-
cies including chick cartilage, bovine aorta and lung,
human placenta, and piglet skin (Stassen 1976; Kuivaniemi
et al. 1984; Cronlund and Kagan 1986; Shackleton and
Hulmes 1990). The molecular mass of the enzyme from all
these sources was found to be 30 kDa (Panchenko et al.
1996; Kagan and Li 2003). LysOX has been cloned from
rat (Trackman et al. 1990, 1991), human (Hamalainen et al.
1991, 1993; Mariani et al. 1992), chick (Wu et al. 1992),
and mouse (Contente et al. 1993) tissues. The mRNA for
human LysOX is found as multiple species with sizes of
5.5, 4.3, 2.4, and 2.0 kilobases due to the use of alternate
polyadenylation sites and partially to the existence of
multiple transcription initiation sites (Mariani et al. 1992;
Boyd et al. 1995). The human LysOX gene is located on
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chromosome 5q23.5–31.2 (Hamalainen et al. 1991, 1993;
Mariani et al. 1992; Wu et al. 1992; Contente et al. 1993;
Boyd et al. 1995) and encodes a 417 amino acid poly-
peptide, of which the first 21 residues correspond to the
signal peptide (Hamalainen et al. 1991; Mariani et al.
1992). The mouse LysOX gene has been mapped to
chromosome 18 (Contente et al. 1993; Boyd et al. 1995;
Mock et al. 1992; Chang et al. 1993).
Substrate and activity of LysOX
LysOX is a copper-dependent secreted amine oxidase that
oxidatively deaminates specific peptidyl lysine and
hydroxylysine residues of collagen and lysine in elastin in
the presence of molecular oxygen (Kagan 1986; Pinnell
and Martin 1968; Bateman et al. 1986; Reiser et al. 1992).
LysOX can oxidize non-ECM lysine rich proteins such as
histone-H1 as well as various lysine-rich synthetic peptides
including basic fibroblast growth factor (bFGF) (Kagan
et al. 1983; Giampuzzi et al. 2003a; Li et al. 2003). As a
byproduct of the catalytic reaction, reactive aldehydes and
hydrogen peroxide are generated by the LysOX that may
contribute to some of the novel roles of LysOX observed in
the wound healing, cell migration, motility, proliferation,
and differentiation (Li et al. 2000, 2003; Fushida-Takem-
ura et al. 1996; Nelson et al. 1988; Palamakumbura et al.
2004).
The resulting peptidyl aldehydes condense spontane-
ously to form various bi-,tri-,and tetrafunctional intra- and
inter molecular cross links (Kagan et al. 1984; Siegel
1974). In collagens, the lysine and hydroxylysine-derived
cross-links are essential for providing the tensile strength
and mechanical stability of the collagen fibrils and other
supramolecular assemblies (Light and Bailey 1980; Bailey
2001) (Fig. 1).
Collagen are the most abundant proteins in mammals,
with at least 35 members divided into 9 families. This
multigen family disperses gene throughout 15 or more
chromosomes. Collagen molecules consist of three peptide
Fig. 1 The catalytic activity of LysOX: LysOX oxidatively deami-
nates a peptidyl lysine to generate a peptidyl allysine which
spontaneously reacts with another peptidyl lysine or allysine to form
a covalent cross-link between proteins (Kagan 1986; Kagan and Cai
1995)
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Siddikuzzaman et al.
chains called a chains, and contain at least one triple-
helical collagenous domain with repeating (Gly-X–Y)n
sequences, i.e., a glycine residue as every third amino acid,
with the frequent presence of proline and 4-hydroxyproline
in the X and Y positions, respectively. After post-transla-
tion modification in the extracellular space, the precursor
of fibrillar collagen, called procollagen, undergoes prote-
olytic conversion to form collagen molecules. Collagen
molecules form fibrils and interact with non-collagenous
and collagenous protein, while they assemble into supra-
molecule structure where the fibrils are stabilized by the
formation of intra- and intermolecular cross-links (Byers
2001; Myllyharju and Kivirikko 2001; Koch et al. 2001;
Fitzgerald et al. 2001).
Elastin is a highly insoluble protein component of the
elastic fibers found in the ECM to provide elasticity and
resilience to tissues requiring the ability to deform
reversibly. Tissues rich in elastin include the aorta and
large blood vessels (28–32% of the dry mass), lung
(3–7%), elastic ligaments (50%), tendons (4%), and skin
(2%) (Vrhovski and Weiss 1998; Debelle and Tamburro
1999). Tropoelastin, the precursor of elastin, is encoded by
a single gene located on chromosome 7q11in humans and
its alternative splicing results in at least 11 variants
(Vrhovski and Weiss 1998). After minor post-translation
modifications, tropoelastin is oxidized and covalently
cross-linked by LysOX catalytic activity (Gibson et al.
1996; Kagan 1986) after which it is assembled into
microfibers (Gibson et al. 1996).
LysOX is a tumor suppressor
The first direct evidence of the tumor suppressor activity of
LysOX was demonstrated (Contente et al. 1990), and it
identified a markedly down-regulated cDNA species upon
transformation of mouse NIH 3T3 cells with LTR-c-H-ras.
The expression level of this cDNA was restored when the
transformed cell line (RS485) was treated with interferon
to obtain a persistent revertant cell line (PR4). This cDNA
species was named as ras recision gene (rrg). Contente
et al. (1990) were the first to isolate an mRNA (called the
ras recision gene) that was downregulated in ras-trans-
formed fibroblasts. Persistent treatment of ras-transformed
fibroblasts with IFNa/b yielded a revertant of the ras-
transformed phenotype and a corresponding re-expression
of the ras recision gene. It was later determined that the ras
recision gene was, in fact, LysOX (Kenyon et al. 1991).
Subsequently, it also demonstrated that the experimental
downregulation of LysOX in normal rat kidney fibroblasts
(NRKF) led to increased cellular proliferation and
anchorage-independent growth, loss of PDGF and IGF-1
regulation, and constitutive activation of ras (Giampuzzi
Lysyl oxidase: a potential target for cancer therapy
et al. 2001). A non-orthotopic injection of LysOX knock
out NRKF cells demonstrated increased tumorigenicity and
metastasis. These investigators went on to demonstrate that
the constitutive activation of ras (by downregulation of
LysOX) led to increased expression of b-catenin and cyclin
D1 through a noncanonical ras signaling pathway (Gia-
mpuzzi et al. 2003b). Moreover, re-expression of LysOX in
ras-transformed fibroblasts led to a decrease in the activa-
tion of NF-jB, a potent transcription factor capable of
regulating cell growth and neoplastic transformation (Jeay
et al. 2003). The deactivation of NF-jB was not due to
direct interaction with LysOX, but by the inhibition of Akt/
PI3K activation and membrane localization (a ras activated
pathway). The most unanticipated results demonstrated that
it was not LysOX catalytic activity that mediated the
suppression of neoplastic transformation signaling in
fibroblasts, but it was the 18-kDa LysOX-PP cleaved from
pro-LysOX by BMP-1 (Palamakumbura et al. 2004).
Although intracellular activity of the cleaved amino ter-
minus of proLysOX is a recent finding, it is not novel as the
cleaved procollagen N-propeptide has also been shown to
function intracellularly to alter protein synthesis and
phosphorylation, as well as cellular adhesion (Oganesian
et al. 2006). In addition to oncogene-transformed fibro-
blasts, a decrease in LysOX activity has also been observed
in fibrosarcoma, choriocarcinoma, and rhabdomyosarcoma
cell lines compared with normal fibroblast cell lines, which
was subsequently shown to be due to low quantities of
LysOX mRNA (Kuivaniemi et al. 1986a, b; Hämäläinen
et al. 1995). With the introduction of microarray analysis,
LysOX has been shown to be modulated in various cancer
cell lines and their corresponding tumor tissues. Thus, the
majority of reports indicating alterations in LysOX
expression have been limited to mRNA a transcript level,
which does not always correlate with catalytic activity
(Uzel et al. 2000). To date, a decrease in LysOX mRNA
and/or protein has been observed in basal and squamous
cell, bronchogenic, colon, esophageal, gastric, head and
neck squamous cell, pancreatic, and prostatic carcinomas,
as well as melanoma. However, only two reports have
definitively demonstrated a tumor suppressor role for
LysOX using in vitro/in vivo model systems. Downregu-
lation of LysOX (stable antisense expression) in
keratinocytes induced their invasion into the dermis of an
in vitro skin equivalent model (Bouez et al. 2006).
Interestingly, treatment of normal keratinocytes with
bAPN did not induce invasion and suggests a role for
LysOX-PP in tumor suppression in this model. Alterna-
tively, LysOX protein may be capable of binding to novel
target proteins outside of the catalytic domain to alter cell
signaling involved in tumor progression. Stable transfec-
tion of full-length LysOX cDNA into an intestinal-type
gastric cancer cell line decreased proliferation and
anchorage-independent cell growth, as well as tumorigen-
esis in non-orthotopically injected nude mice (Kaneda et al.
2004a, b). These studies have shown that LysOX acts as a
potent tumor suppressor gene in fibroblasts, basal, and
squamous cell and gastric carcinomas that occur through
inhibiting intracellular signaling pathways known to induce
neoplastic transformation. It remains to be determined
whether the tumor suppressor activity of LysOX is as
intimately involved in other cancers where down regulation
of LysOX mRNA has been observed. Altered expression of
other LysOX family members has been identified as well.
LysOXL mRNA expression is downregulated in renal cell
carcinoma cell lines in which the Von Hippel-Lindau
(VHL) gene has been mutated, suggesting that loss of
LysOXL expression is associated with oncogenesis of type
2B VHL disease (mutations in the elongin-binding region)
(Tsuchiya et al. 2005). In addition, LysOXL expression
was upregulated in wild-type p53 reconstituted lung ade-
nocarcinoma cell lines (Kannan et al. 2001). Down-
regulation of LysOXL mRNAwas observed in head and
neck squamous cell carcinoma cell lines; however, more
in-depth analyses are required to establish a tumor sup-
pressor role for LysOXL and LysOXL2 in these cancers.
The tumor suppressor activity of LysOX has been mapped
to the pro-peptide region, and LysOX-PP inhibits tumor
formation by breast cancer cells in mice (Paola et al. 2008)
(Table 1).
LysOX is a metastasis promoter
The upregulation of LysOX mRNA in various cancer cell
lines and their corresponding tumor tissues was demon-
strated by microarray technology. To date, an increase in
LysOX mRNA and/or protein has been observed in breast,
central nervous system cancer cell lines, head and neck
squamous cell, prostatic, clear cell renal cell, and lung
carcinomas, and in melanoma and osteosarcoma cell lines,
compared with their normal or non-aggressive neoplastic
counterparts. Statistically significant clinical correlations
between LysOX expression and tumor progression have
been observed in breast (Erler et al. 2006), head and neck
squamous cell (Erler et al. 2006), prostatic (Lapointe et al.
2004), and clear cell renal cell carcinomas (Stassar et al.
2001). LysOXL1 gene regulation is affected by an epige-
netic mechanism that can be reversed by an inhibitor of
DNA methyltransferase activity (Romain et al. 2010).The
expression of high levels of LysOX mRNA and/or protein
was a poor prognostic factor and was associated with
poorly differentiated, high-grade tumors, increased recur-
rence rates, and decreased overall survival. The role of
LysOX in tumor progression has been most extensively
studied in breast cancer using in vitro models of migration/
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 Siddikuzzaman et al.

Table 1 LysOX as a tumor suppressor gene: in vitro and in vivo studies

In vivo In vitro

Inhibition of ras transformation (Di Donato et al. 1997)
Stromal reactions in cancer (Bouez et al. 2006)
Inhibition of breast cancer (Urashima et al. 2008)
Inhibition of Choriocarcinoma (Hämäläinen et al. 1995)
In Esophageal cancer (He et al. 2002)
Gastric cancer (Kaneda et al. 2004a, b)
Lung cancer (Wu et al. 2007)
Multiple endocrine neoplasia (MEN) (Watanabe et al. 2002)
Ovarian cancer (Kaneda et al. 2004a, b)
Prostate cancer (Ren et al. 1998)
Rhabdomyosarcoma (Hämäläinen et al. 1995)
Inhibition of ras (Csiszar et al. 1996)
Inhibition of basal and squamous cell carcinoma (Bouez et al. 2006)
Inhibition of bone cancer (Buchinger et al. 2008)
Choriocarcinoma (Hämäläinen et al. 1995)
Inhibition of Colon Cancer (Csiszar et al. 2002)
Fibrosarcoma (Hämäläinen et al. 1995)
Head and neck squamous cell carcinoma (HNSCC) (Rost et al. 2003)
Lung cancer (Shames et al. 2006)
Pancreatic cancer (Wu et al. 2007)

invasion and in in vivo tumorigenesis and metastasis

mouse models. In malignant human breast carcinomas,
LysOX was highly expressed in myofibroblasts and myo-
epithelial cells surrounding the in situ tumor and in the
reactive fibrosis facing the invasion front of infiltrating
tumors (Peyrol et al. 1997). Upregulation of LysOXL2
mRNA and/or protein has been reported in breast, esoph-
ageal, head and neck squamous cell, pancreatic, and
prostatic carcinomas, melanoma, and E1A-immortalized
kidney epithelial cell lines, compared with normal or
poorly aggressive neoplastic counterparts. Chung and col-
leagues demonstrated that increased LysOXL2 expression
(along with the expression of 74 other genes) was signifi-
cantly associated with high-risk head and neck squamous
cell carcinoma and could be used as a predictive biomarker
for high-risk patients (Chung et al. 2006). It has been
demonstrated that stable expression of LysOXL2 in poorly
invasive/non-metastatic MCF-7 breast cancer cells pro- Fig. 2 LysOX regulation
duced estrogen-dependent tumors in orthotopically injected
nude mice with many fibrotic foci and cells that were Peltonen et al. 1983; Royce et al. 1980). The transport
capable of invading the tumor pseudocapsule and into through the Golgi and to the cell membrane probably takes
surrounding blood vessels, nerves, and muscle tissue (Akiri place in vesicles formed by budding of, and fusion with,
et al. 2003). Taken together, these reports demonstrate the the sub-cellular membranes (Kosonen et al. 1997; Rucker
potential of LysOXL2 to promote metastatic tumor pro- et al. 1998). Human LysOX is synthesized as a 48-kDa
gression; however, more in-depth analyses are required to prepro-enzyme with a 21-amino-acid signal sequence at the
determine the mechanism in these cancers. In contrast, very N terminus (Trackman et al. 1992). Following the N-ter-
few reports have demonstrated altered expression of Lys- minal glycosylation, the signal peptide is cleaved off and
OXL3 and LysOXL4 in cancers. At this time, very little is the copper co-factor incorporates into the protein, resulting
known about the biological function of these LysOX in an intermediary 50 kDa pro-enzyme in the Golgi appa-
family members in normal cell processes (Fig. 2; Table 2). ratus which is then secreted to the extracellular space
(Trackman et al. 1992; Layman et al. 1972). There the
protein can be activated by a proteolytic cleavage between
Biosynthesis of LysOX residues G168 and D-169, which is catalyzed by procol-
lagen C-proteinase/BMP-1 (bone morphogenetic protein-1)
It has been demonstrated that the LysOX protein is known (Cronshaw et al. 1995). The proteinase activation yields a
to be secreted into the extracellular space (Byers et al. mature enzyme of 30 kDa (Panchenko et al. 1996; Kagan
1980; Kuivaniemi et al. 1986a; Layman et al. 1972; and Li 2003) and 18 kDa N-terminal propeptide fragment.

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Lysyl oxidase: a potential target for cancer therapy

Table 2 LysOX as a metastasis

promoter gene: in vitro and in
vivo studies
In vivo
Promotion of tumor progression in breast cancer
(reviewed in Payne et al. 2007).
Promotion of tumor progression in brain cancer
(Freije et al. 2004)
Promotion of tumor progression in head and neck
squamous cell carcinoma (HNSCC)
(Erler et al. 2006; Le et al. 2007)
Promotion of tumor progression in lung cancer
(Borczuk et al. 2005)
Promotion of tumor progression in renal cell
carcinoma (RCC) (Korenaga et al. 2005)
In vitro
Promotion of tumor progression in bone cancer
(Fuchs et al. 2000)
Promotion of tumor progression in brain cancer
(Ross et al. 2000)
Promotion of tumor progression in breast cancer
(reviewed in Payne et al. 2007)
Promotion of tumor progression in cervical cancer
(Erler et al. 2006)
Promotion of tumor progression in prostate
cancer (Stewart et al. 2009)

Proteolytic processing and activation of LysOX
Mammalian BMP-1 proteinase family members (BMP-1,
mTLD, mTLL-1, mTLL-2) have LysOX pro-enzyme pro-
cessing activity (Uzel et al. 2001). These proteins are
encoded by two genes. By alternative splicing, BMP1 gene
codes BMP-1 and mammalian tolloid (mTLD) while the
tolloid-related proteinases, tolloid-like 1 (mTLL-1) and
tolloid-like 2 (mTLL-2) are encoded by mTll-1 gene (Uzel
et al. 2001; Kessler et al. 1996; Prockop et al. 1998;
Takahara et al. 1994). BMP-1 is a multifunctional enzyme
as it was also discovered to have procollagen C-proteinase
activity, and moreover its amino acid sequence was iden-
tical to the one of procollagen C-proteinase (Kessler et al.
1996). In mouse embryonic fibroblasts, all four BMP-1
proteinases show procollagen-C proteinase activity and
cleave the 50-kDa LysOX precursor in vitro. Nevertheless,
BMP-1, above all members of the family, showed the
highest proteinase activity on LysOX (Uzel et al. 2001).
et al. 1999), and myofibroblast-like cells in the flexor
reticulum of carpal tunnel syndrome patients (Bose et al.
2000). In rodents TGF-b1 induced up-regulation of LysOX
mRNA and protein levels was found in neonatal rat lung
fibroblasts (Boak et al. 1994; Koslowski et al. 2003), the
osteoblastic mouse cell line MC3T3-E1 (Shibanuma et al.
1993; Feres-Filho et al. 1995). TGF-b regulation of LysOX
activity was also reported in rat aortic smooth muscle cells
(Shanley et al. 1997; Gacheru et al. 1997). Platelet-derived
growth factor (PDGF) also up-regulated LysOX mRNA
levels in rabbit retinal pigment epithelial cells (Omori et al.
2002) and rat vascular smooth muscle cells (Smith-Mungo
and Kagan 2002; Green et al. 1995). Application of insulin-
like growth factor-I (IGF-I) in rat oral tissue increased
LysOX protein level (Trackman et al. 1998). Amongst
hormones, follicle-stimulating hormone (FSH) decreased
LysOX mRNA expression and activity in rat granulose
cells, but testosterone increased both LysOX mRNA level
and activity (Bronson et al. 1987; Harlow et al. 2003; Slee
et al. 2001).

Transcriptional regulation of LysOX

LysOX mRNA expression and protein activity are highly
responsive to a variety of cytokines, growth factors, and
intercellular messengers (Csiszar 2001). LysOX mRNA
was down-regulated by bFGF in human gingival fibroblasts
(Hong and Trackman 2002), and LysOX mRNA in rabbit
retinal pigment epithelial cells (Feres-Filho et al. 1996;
Omori et al. 2002), and in mouse osteoblastic cells (Feres-
Filho et al. 1996). It was also down-regulated by inter-
feron- (IF-) in rat aortic smooth muscle cells (Tan et al.
1996; Song et al. 2000), and by prostaglandin E2 (PGE2) in
human embryonic smooth muscle cells (Roy et al. 1996),
and from neonatal rat lung fibroblasts (Boak et al. 1994;
Choung et al. 1998). Transforming growth factor-b1 (TGF-
b1) up-regulated both LysOX mRNA and protein levels in
human embryonic lung fibroblasts (Roy et al. 1996;
Choung et al. 1998), human gingival fibroblasts (Hong
Dietary copper and LysOX production
LysOX activity showed that it is influenced directly by the
amount of dietary copper over a wide physiologic range of
intakes in growing animals (Opsahl et al. 1982). It also
reported that lysyl oxidase activity varies by as much as
five- to sixfold in response to dietary copper, ranging from
0 added Cu to 25 mg Cu/g diet (Opsahl et al. 1982). This
observation has intrigued us because there is no compelling
reason why an excess of dietary copper per se should
increase LysOX activity above what might be needed for
normal cross-linking (Opsahl et al. 1982; Romero-Chap-
man et al. 1990; Rucker et al. 1996). For example, for
optimal growth in chickens the copper requirement is
5–10 mg Cu/g diet (Opsahl et al. 1982). Decreased colla-
gen cross-linking does not occur until the copper intake is
substantially \1 mg Cu/g diet. Copper deficiency also has

123

little or no effect on LysOX protein or LysOX mRNA
concentrations in tissues (Rucker et al. 1996).
LysOX expression is regulated by hypoxia-inducible
factors (HIFs), and, hence, LysOX expression is often up-
regulated in hypoxic breast and head and neck tumors and
also in cardiovascular diseases (Cristina et al. 2008) and
regulation of LysOX by statins could contribute to vascular
protection and to the cardiovascular risk reduction (Cristina
et al. 2009). Patients with high LysOX-expressing tumors
have poor overall survival. Furthermore, inhibition of
LysOX has been demonstrated to eliminate metastases in
mice. Targeting LysOXL2 with an inhibitory monoclonal
antibody (AB0023) has been reported efficacious in both
primary and metastatic xenograft models of cancer, as well
as in liver and lung fibrosis models (Barry-Hamilton et al.
2010) and also pro-BAPNs showed good levels of in vitro
hypoxia-selective inhibition of LysOX activity (Carlotta
et al. 2009). The LysOXL1 genetic predisposition is lim-
ited to exfoliation glaucoma and does not include normal
tension glaucoma (Wolf 2010).
In conclusion, our present review reveals that Lysyl
oxidase plays a significant role in cancer therapy. Several
studies using plant products and natural products show that
targeting LysOX could significantly reduce tumor pro-
gression, metastasis, and angiogenesis. Some of the natural
products that have shown significant results involve Bio-
phytum sensitivum, amentoflavone, and b-carotene
(Guruvayoorappan and Kuttan 2007, 2008a, b). The dis-
covery of new drugs that can inhibit of the LysOX enzyme
may be useful in preventing tumor progression and
metastasis (Erler et al. 2009), and it can lead to open new
approaches and directions for cancer therapy.
Acknowledgments The Valuable support of Dr. Patrick Gomez,
Director, School of Biotechnology and Health Sciences, Karunya
University is greatfully acknowledged.
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