Role of the autotaxin–lysophosphatidate axis in cancer resistance to chemotherapy and radiotherapy

doi:10.1016/j.bbalip.2012.08.015

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids

Volume 1831, Issue 1, January 2013, Pages 74-85

https://doi.org/10.1016/j.bbalip.2012.08.015 Get rights and content

Abstract

High expression of autotaxin in cancers is often associated with increased tumor progression, angiogenesis and metastasis. This is explained mainly since autotaxin produces the lipid growth factor, lysophosphatidate (LPA), which stimulates cell division, survival and migration. It has recently become evident that these signaling effects of LPA also produce resistance to chemotherapy and radiation-induced cell death. This results especially from the stimulation of LPA₂ receptors, which depletes the cell of Siva-1, a pro-apoptotic signaling protein and stimulates prosurvival kinase pathways through a mechanism mediated via TRIP-6. LPA signaling also increases the formation of sphingosine 1-phosphate, a pro-survival lipid. At the same time, LPA decreases the accumulation of ceramides, which are used in radiation therapy and by many chemotherapeutic agents to stimulate apoptosis. The signaling actions of extracellular LPA are terminated by its dephosphorylation by a family of lipid phosphate phosphatases (LPP) that act as ecto-enzymes. In addition, lipid phosphate phoshatase-1 attenuates signaling downstream of the activation of both LPA receptors and receptor tyrosine kinases. This makes many cancer cells hypersensitive to the action of various growth factors since they often express low LPP1/3 activity. Increasing our understanding of the complicated signaling pathways that are used by LPA to stimulate cell survival should identify new therapeutic targets that can be exploited to increase the efficacy of chemo- and radio-therapy. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.

Highlights

► Autotaxin and LPA receptors are upregulated in metastatic cancers. ► LPA receptors, particularly the LPA₂ subtype convey resistance against apoptosis. ► LPA is removed from the extracellular compartment by lipid phosphate phosphatases. ► Expression of lipid phosphate phosphatases is often low in cancers. ► The ATX–LPA receptor–LPP axis influences the chemo- and radiation-resistance of cancers.

Section snippets

Introduction and overview

The involvement of the lipid mediator lysophosphatidate (LPA) in regulating tumor progression, angiogenesis and metastasis has been increasingly recognized over the last decade. Much of the impetus for this started with the identification of autotaxin (ATX) as an extracellular lysophospholipase D, whose major signaling effect is to generate extracellular LPA [1], [2], [3]. ATX was originally identified in 1992 in the media derived from A2058 human melanoma cells. Stracke et al. showed that

Role of autotaxin and lysophosphatidate in tumor biology

Lysophosphatidylcholine (LPC) is the most abundant phospholipid in blood plasma where it reaches concentrations of about 200 μM in human beings [12]. The liver secretes unsaturated LPC [13] and presumably, this depends on the activity of a phospholipase A₁. It is probable that other organs also have this ability to secrete unsaturated LPC. Saturated LPC in the circulation is produced mainly by lecithin:cholesterol acyltransferase acting on the phosphatidylcholine in high density lipoproteins.

Other routes of LPA formation

Apart from the actions of autotaxin, other pathways can produce extracellular LPA (Fig. 1). One such pathway involves secretory phospholipase A2 (sPLA2), which produces LPA from phosphatidate (PA). This latter lipid is present in micro-vesicles released during inflammation reactions [29]. Also, group VIA phospholipase A₂ (Ca^2 + independent phospholipase A2β, iPLA2β) produces extracellular LPA in human epithelial ovarian cancer cells [30], [31]. The importance of this reaction in ovarian cancer

Turnover of extracellular LPA through the ecto-activities of lipid phosphate phosphatases

Plasma LPA concentrations are normally < 1 μM, but they have been reported to reach > 10 μM in ovarian cancer and this depends mainly on LPA production by ATX [8]. LPA is also degraded rapidly as expected for an important bioactive compound (Fig. 1). This is achieved through the actions of a family of three enzymes that are called lipid phosphate phosphatases (LPPs) [39]. These enzymes dephosphorylate a large variety of bioactive lipid phosphates and pyrophosphates, including LPA [40]. The location

Role of lipid phosphate phosphatases in regulating cell signaling downstream of the activation of growth factor receptors

The LPPs are expressed on internal membranes including the endoplasmic reticulum [42], [54] and the Golgi network [55]. It is assumed that the catalytic sites face the lumenal side of these membranes. This internal LPP activity appears to regulate the turnover of lipid phosphates that are formed downstream of the activation of GPCR, including the LPA receptors, as well as receptor tyrosine kinases. This action controls the concentrations of the lipid phosphates relative to their

Effects of LPA signaling in controlling the proapoptotic effects of ceramides versus the survival signals from sphingosine 1-phosphate

Many chemotherapeutic agents (including Taxol, doxorubicin and vincristine) and radiation therapy increase ceramide formation as part of their therapeutic actions in stimulating cell death (Fig. 3) [89], [90], [91], [92], [93], [94], [95]. Ceramides are sphingolipids that release cytochrome C from mitochondria and activate caspases to initiate apoptosis [93], [96]. The increased balance of ceramide versus S1P signaling is considered to be an important “rheostat” that favors the death versus

Overexpression of LPA receptor subtypes in different types of cancers

LPA elicits many of its cellular actions via the stimulation of specific GPCRs. LPA activates two clusters of GPCR. To date, six GPCR have been validated as specific targets of LPA. These include three GPCR encoded by the Endothelial Differentiation Gene family and designated LPA₁, LPA₂, and LPA₃. Three other GPCR that include LPA₄(GPR23/P2Y9), LPA₅(GPR92), and LPA₆(P2Y5) are related to the purinergic family of GPCR. There are three other GPCR including GPR87 [103], [104], P2Y10 [105], and

Role of LPA receptors in mediating resistance to genotoxic agents (chemo and radiation therapy)

There is evidence for the oncogenic transforming action of LPA GPCR. Taghavi et al. [10] have evaluated the role of LPA_1/2/3/4 in malignant transformation and found that the rank order of transforming activity was LPA₂ > LPA₁ > LPA₄. LPA₃ did not promote the growth in soft-agar of mouse embryonic fibroblasts immortalized with the Tbx2 transcriptional suppressor and c-Myc. When these fibroblasts were injected into nude mice the rank order of survival was LPA₁ < LPA₂ < LPA₄ whereas, LPA₃ cells did not

Unique aspects of LPA₂ receptor signaling underlying radiation and chemoresistance

Tumor cells upregulate lipid synthesis as a requirement for increased cell proliferation. Lipogenesis is controlled by the sterol regulatory element binding proteins (SREBP). Mukherjee and colleagues recently showed in carcinoma cells, but not in nontransformed cells, that LPA upregulates the transcriptional activity of SREBP [146], which is the rate-limiting step in lipogenesis. The 5′ adenosine monophosphate-activated protein kinase (AMPK) plays a role in cellular energy homeostasis. The net

Concluding remarks

The treatment of various cancers often fails due to the development of resistance to the actions of various chemotherapies and radiotherapy and patients die mainly because of the spread of metastases. This resistance depends largely on the effects of various growth factors including estrogens, EGF, PDGF, VEGF etc. that enable cancer cells to avoid cell death. We propose that another growth factor called LPA contributes to these problems of chemo-resistance. LPA is generated outside the cells

Acknowledgements

The work was supported by grants to DNB from the Canadian Institutes of Health Research, the Alberta Cancer Foundation and the Canadian Breast Cancer Foundation, by grants to GT from the National Cancer Institute, CA92160, AI80405 from the National Institute of Allergy Medical Countermeasures Radiological and Nuclear Threats Program, and by the Harriet Van Vleet Endowment for Basic Oncology Research.

References (164)

A. Tokumura et al.
Identification of human plasma lysophospholipase D, a lysophosphatidic acid-producing enzyme, as autotaxin, a multifunctional phosphodiesterase
J. Biol. Chem.
(2002)
L.A. van Meeteren et al.
Regulation and biological activities of the autotaxin–LPA axis
Prog. Lipid Res.
(2007)
M.L. Stracke et al.
Identification, purification, and partial sequence analysis of autotaxin, a novel motility-stimulating protein
J. Biol. Chem.
(1992)
N. Samadi et al.
Regulation of lysophosphatidate signaling by autotaxin and lipid phosphate phosphatases with respect to tumor progression, angiogenesis, metastasis and chemo-resistance
Biochimie
(2011)
D.N. Brindley
Hepatic secretion of lysphosphatidylcholine: a novel transport system for polyunsaturated fatty acids and choline
J. Nutr. Biochem.
(1993)
J. Aoki et al.
Serum lysophosphatidic acid is produced through diverse phospholipase pathways
J. Biol. Chem.
(2002)
Z. Fulkerson et al.
Binding of autotaxin to integrins localizes lysophosphatidic acid production to platelets and mammalian cells
J. Biol. Chem.
(2011)
M.Y. Hsu et al.
Adenoviral gene transfer of beta3 integrin subunit induces conversion from radial to vertical growth phase in primary human melanoma
Am. J. Pathol.
(1998)
L.M. Yuelling et al.
Autotaxin (ATX): a multi-functional and multi-modular protein possessing enzymatic lysoPLD activity and matricellular properties
Biochim. Biophys. Acta
(2008)
S. Jansen et al.
Domain interplay mediated by an essential disulfide linkage is critical for the activity and secretion of the metastasis-promoting enzyme autotaxin
J. Biol. Chem.
(2009)

O. Fourcade et al.

Secretory phospholipase A2 generates the novel lipid mediator lysophosphatidic acid in membrane microvesicles shed from activated cells

Cell

(1995)

X. Zhao et al.

Caspase-3-dependent activation of calcium-independent phospholipase A2 enhances cell migration in non-apoptotic ovarian cancer cells

J. Biol. Chem.

(2006)

N.A. Moughal et al.

Nerve growth factor signaling involves interaction between the Trk A receptor and lysophosphatidate receptor 1 systems: nuclear translocation of the lysophosphatidate receptor 1 and Trk A receptors in pheochromocytoma 12 cells

Cell. Signal.

(2004)

F. Gobeil et al.

Modulation of pro-inflammatory gene expression by nuclear lysophosphatidic acid receptor type-1

J. Biol. Chem.

(2003)

G.D. Girnun et al.

Synergy between PPARgamma ligands and platinum-based drugs in cancer

Cancer Cell

(2007)

J. Yue et al.

Mice with transgenic overexpression of lipid phosphate phosphatase-1 display multiple organotypic deficits without alteration in circulating lysophosphatidate level

Cell. Signal.

(2004)

D. Brindley et al.

Phosphatidate degradation: phosphatidate phosphatases (lipins) and lipid phosphate phosphatases

Biochim. Biophys. Acta

(2009)

S. Milstien et al.

Targeting sphingosine-1-phosphate: a novel avenue for cancer therapeutics

Cancer Cell

(2006)

Y. Zhao et al.

Intracellular generation of sphingosine 1-phosphate in human lung endothelial cells: role of lipid phosphate phosphatase-1 and sphingosine kinase 1

J. Biol. Chem.

(2007)

A. Martin et al.

Decreased activities of phosphatidate phosphohydrolase and phospholipase D in Ras and tyrosine kinase (fps) transformed fibroblasts

J. Biol. Chem.

(1993)

D. Barila et al.

The Dri 42 gene, whose expression is up-regulated during epithelial differentiation, encodes a novel endoplasmic reticulum resident transmembrane protein

J. Biol. Chem.

(1996)

M. Kai et al.

Cloning and characterization of two human isozymes of Mg2 +‐independent phosphatidic acid phosphatase

J. Biol. Chem.

(1997)

S. Pyne et al.

Lysophosphatidic acid and sphingosine 1-phosphate biology: the role of lipid phosphate phosphatases

Semin. Cell Dev. Biol.

(2004)

F. Alderton et al.

G-protein-coupled receptor stimulation of the p42/p44 mitogen-activated protein kinase pathway is attenuated by lipid phosphate phosphatases 1, 1a, and 2 in human embryonic kidney 293 cells

J. Biol. Chem.

(2001)

C. Pilquil et al.

Lipid phosphate phosphatase-1 regulates lysophosphatidate-induced fibroblast migration by controlling phospholipase D2-dependent phosphatidate generation

J. Biol. Chem.

(2006)

I. Garcia-Murillas et al.

Lazaro encodes a lipid phosphate phosphohydrolase that regulates phosphatidylinositol turnover during Drosophila phototransduction

Neuron

(2006)

S. Ghosh et al.

Raf-1 kinase possesses distinct binding domains for phosphatidylserine and phosphatidic acid. Phosphatidic acid regulates the translocation of Raf-1 in 12-O-tetradecanoylphorbol-13-acetate-stimulated Madin–Darby canine kidney cells

J. Biol. Chem.

(1996)

M.A. Rizzo et al.

Phospholipase D and its product, phosphatidic acid, mediate agonist-dependent raf-1 translocation to the plasma membrane and the activation of the mitogen-activated protein kinase pathway

J. Biol. Chem.

(1999)

C. Delon et al.

Sphingosine kinase 1 is an intracellular effector of phosphatidic acid

J. Biol. Chem.

(2004)

D.Y. Noh et al.

Overexpression of phospholipase D1 in human breast cancer tissues

Cancer Lett.

(2000)

S.M. Mandala

Sphingosine-1-phosphate phosphatases

Prostaglandins Other Lipid Mediat.

(2001)

K.E. Morris et al.

Lipid phosphate phosphatase-2 activity regulates S-phase entry of the cell cycle in Rat2 fibroblasts

J. Biol. Chem.

(2006)

M. Serrano et al.

Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a

Cell

(1997)

R. Martinez et al.

Doxorubicin induces ceramide and diacylglycerol accumulation in rat hepatocytes through independent routes

Toxicol. Lett.

(2009)

A. Gomez-Munoz et al.

Cell-permeable ceramides inhibit the stimulation of DNA synthesis and phospholipase D activity by phosphatidate and lysophosphatidate in rat fibroblasts

J. Biol. Chem.

(1994)

M. Umezu-Goto et al.

Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production

J. Cell Biol.

(2002)

S.W. Nam et al.

Autotaxin (NPP-2), a metastasis-enhancing motogen, is an angiogenic factor

Cancer Res.

(2001)

M. Umezu-Goto et al.

Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production

J. Cell Biol.

(2002)

S.Y. Yang et al.

Expression of autotaxin (NPP-2) is closely linked to invasiveness of breast cancer cells

Clin. Exp. Metastasis

(2002)

R. Bekele et al.

Role of autotaxin and lysophosphatidate in cancer progression and resistance to chemotherapy and radiotherapy

Clin. Lipidol.

(2012)

P. Taghavi et al.

In vitro genetic screen identifies a cooperative role for LPA signaling and c-Myc in cell transformation

Oncogene

(2008)

G. Tigyi

Aiming drug discovery at lysophosphatidic acid targets

Br. J. Pharmacol.

(2010)

W.H. Moolenaar et al.

The ins and outs of lysophosphatidic acid signaling

Bioessays

(2004)

C.G. Gaetano et al.

Inhibition of autotaxin production or activity blocks lysophosphatidylcholine-induced migration of human breast cancer and melanoma cells

Mol. Carcinog.

(2009)

N. Samadi et al.

Autotaxin protects MCF-7 breast cancer and MDA-MB-435 melanoma cells against Taxol-induced apoptosis

Oncogene

(2009)

H.M. Albers et al.

Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation

Proc. Natl. Acad. Sci. U. S. A.

(2010)

G. Ferry et al.

S32826, a nanomolar inhibitor of autotaxin: discovery, synthesis and applications as a pharmacological tool

J. Pharmacol. Exp. Ther.

(2008)

J. Gierse et al.

A novel autotaxin inhibitor reduces lysophosphatidic acid levels in plasma and the site of inflammation

J. Pharmacol. Exp. Ther.

(2010)

A.L. Parrill et al.

Autotaxin inhibition: challenges and progress toward novel anti-cancer agents

Anticancer Agents Med Chem.

(2008)

J. Hausmann et al.

Structural basis of substrate discrimination and integrin binding by autotaxin

Nat. Struct. Mol. Biol.

(2011)

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Citation Excerpt :
In recent years there has been extensive research on autotaxin (ATX), a member of the ectonucleotide pyrophosphatase phosphodiesterase (ENPP) enzyme family (a.k.a. ENPP2), which is responsible for catalyzing the hydrolysis of lysophosphatidyl choline (LPC) and similar lysophospholipids to a growth-factor like bioactive phospholipid, lysophosphatidic acid (LPA) [1–13]. On the cell surface, LPA acts via six transmembrane G-protein coupled receptors, LPAR1-6 (LPAR), to promote a variety of physiological responses, including cell proliferation, migration, motility, survival, and platelet aggregation [6,7,13–15]. Thus, the ATX-LPA signaling pathway has been considered to be at the core of a number of diseases, including fibrotic diseases, cardiovascular diseases, inflammation, and central pain [6,7,10,13,16,17].
The lysophospholipase D autotaxin (ATX) generates lysophosphatidic acid (LPA) that activates six cognate G-protein coupled receptors (GPCR) in cancerous cells, promoting their motility and invasion. Four novel compounds were generated aided by molecular docking guided design and synthesis techniques to obtain new dual inhibitors of ATX and the lysophosphatidic acid receptor subtype 1 (LPAR1). Biological evaluation of these compounds revealed two compounds, 10 and 11, as new ATX enzyme inhibitors with potencies in the range of 218–220 nM and water solubility (>100 µg/mL), but with no LPAR1 inhibitory activity. A QSAR model was generated that included four newly designed compounds and twenty-one additional compounds that we have reported previously. The QSAR model provided excellent predictability of the pharmacological activity and potency among structurally related drug candidates. This model will be highly useful in guiding the synthesis of new ATX inhibitors in the future.
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^☆: This article is part of a Special Issue entitled Advances in Lysophospholipid Research.

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Role of the autotaxin–lysophosphatidate axis in cancer resistance to chemotherapy and radiotherapy☆

Abstract

Highlights

Section snippets

Introduction and overview

Role of autotaxin and lysophosphatidate in tumor biology

Other routes of LPA formation

Turnover of extracellular LPA through the ecto-activities of lipid phosphate phosphatases

Role of lipid phosphate phosphatases in regulating cell signaling downstream of the activation of growth factor receptors

Effects of LPA signaling in controlling the proapoptotic effects of ceramides versus the survival signals from sphingosine 1-phosphate

Overexpression of LPA receptor subtypes in different types of cancers

Role of LPA receptors in mediating resistance to genotoxic agents (chemo and radiation therapy)

Unique aspects of LPA2 receptor signaling underlying radiation and chemoresistance

Concluding remarks

Acknowledgements

J. Biol. Chem.

Prog. Lipid Res.

J. Biol. Chem.

Biochimie

J. Nutr. Biochem.

J. Biol. Chem.

J. Biol. Chem.

Am. J. Pathol.

Biochim. Biophys. Acta

J. Biol. Chem.

Cell

J. Biol. Chem.

Cell. Signal.

J. Biol. Chem.

Cancer Cell

Cell. Signal.

Biochim. Biophys. Acta

Cancer Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Semin. Cell Dev. Biol.

J. Biol. Chem.

J. Biol. Chem.

Neuron

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Cancer Lett.

Prostaglandins Other Lipid Mediat.

J. Biol. Chem.

Cell

Toxicol. Lett.

J. Biol. Chem.

Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production

J. Cell Biol.

Autotaxin (NPP-2), a metastasis-enhancing motogen, is an angiogenic factor

Cancer Res.

Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production

J. Cell Biol.

Expression of autotaxin (NPP-2) is closely linked to invasiveness of breast cancer cells

Clin. Exp. Metastasis

Role of autotaxin and lysophosphatidate in cancer progression and resistance to chemotherapy and radiotherapy

Clin. Lipidol.

In vitro genetic screen identifies a cooperative role for LPA signaling and c-Myc in cell transformation

Oncogene

Aiming drug discovery at lysophosphatidic acid targets

Br. J. Pharmacol.

The ins and outs of lysophosphatidic acid signaling

Bioessays

Inhibition of autotaxin production or activity blocks lysophosphatidylcholine-induced migration of human breast cancer and melanoma cells

Mol. Carcinog.

Autotaxin protects MCF-7 breast cancer and MDA-MB-435 melanoma cells against Taxol-induced apoptosis

Oncogene

Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation

Proc. Natl. Acad. Sci. U. S. A.

S32826, a nanomolar inhibitor of autotaxin: discovery, synthesis and applications as a pharmacological tool

J. Pharmacol. Exp. Ther.

A novel autotaxin inhibitor reduces lysophosphatidic acid levels in plasma and the site of inflammation

J. Pharmacol. Exp. Ther.

Autotaxin inhibition: challenges and progress toward novel anti-cancer agents

Anticancer Agents Med Chem.

Structural basis of substrate discrimination and integrin binding by autotaxin

Nat. Struct. Mol. Biol.

Unique aspects of LPA₂ receptor signaling underlying radiation and chemoresistance