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

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 LPA(2) 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.

Copyright © 2012 Elsevier B.V. All rights reserved.

Figures

Fig. 1

Regulation of extracellular lysophosphatidate turnover and cell signaling. Most of the extracellular LPA is produced by autotaxin from the abundant LPC that is present in extracellular fluids. Additional LPA is produced from phosphatidylcholine or phosphatidate by various phospholipases. Extracellular LPA is degraded by the ecto-activities of the lipid phosphate phosphatases, which are expressed on the plasma membrane of cells. Extracellular LPA can activate signal transduction events through up to nine specific plasma membrane GPRCR. Most of these receptors provide signals for cell growth, migration and survival.

Fig. 2

Lipid phosphate phosphatases attenuate signaling downstream of GPCRs and receptor tyrosine kinases. This effect depends on the phosphatase activity demonstrating that the blocking of signaling depends on the metabolism of a lipid phosphate formed in response to activation of the receptors. The concept is illustrated by the effect of the LPPs in decreasing the accumulation of phosphatidate following the activation of PLD. PA activates sphingosine kinase-1 (SK-1), Sos, Raf and ERK, mTOR, protein PKC-ζ and it inhibits protein phosphatase-1 (PP-1). These actions stimulate cell survival and migration. Many cancer cells show very low expression of LPP1 and LPP3. We propose that this makes them hypersensitive to growth factors such as LPA, S1P, EGF and PDGF, which contribute to chemoresistance.

Fig. 3

Effects of LPA signaling in decreasing the proapoptotic effects of ceramides and increasing the survival signals from sphingosine 1-phosphate. Most chemotherapeutic agents and radiation therapy increase ceramide formation to produce an apoptotic signal. Ceramides block phospholipase D (PLD) activation and thereby the activation of survival and migratory signals that are initiated by phosphatidate (PA). These effects are counteracted by survival signals from LPA, which activates PLD and phosphatidylinositol 3-kinase (PI3K). These actions decrease ceramide production and increase the formation of S1P. These effects decrease the ratio of ceramide to S1P and promote cell survival and chemo-resistance relative to cell death.

Fig. 4

LPA2 receptor conveys increased resistance to radiation-induced apoptosis. In the experiment shown, mouse embryonic fibroblast (MEF) cells were derived from LPA1 and LPA2 double knockout mice and transduced with empty lentivirus vector (LPA1&2−/− MEF) or with the human LPA2 receptor (LPA2 Add-Back MEF). These cells also do not endogenously express LPA3 [159]. Both types of MEF cells were exposed to 15 Gy of γ-irradiation and treated with increasing concentrations of the LPA receptor agonist OTP. Apoptosis was quantified 5 h later using caspase 3/7 activity. Note that radiation alone elicits higher level of apoptosis in LPA1&2−/− MEF compared to LPA2 Add-Back MEF suggesting that LPA2 expression without exogenous ligand increases the radiation resistance of these cells. Also note, that the LPA mimic ligand OTP showed a dose-dependent attenuation of radiation-induced caspase 3/7 activity only in LPA2 Add-Back MEF whereas, it was ineffective in LPA1&2−/− MEF cells. This indicates that activation of LPA2 alone can lead to increased resistance to radiation-induced apoptosis.

Fig. 5

Scheme of the ATX–LPA2 signaling axis in the regulation of chemo- and radiation resistance. Genotoxic chemotherapeutics and radiation activate E2F and p53, which promote the initiation of apoptosis. Siva-1 is an immediate early response gene product regulated by p53 and E2F. In the cytoplasm, Siva-1 binds to Bcl-XL and depletion of this Bcl-2 antiapoptotic protein promotes apoptosis. Siva-1 in the nucleus complexes with p53 and the ubiquitin ligase Mdm2. The polyubiquitinated complex can eventually be degraded by the proteasome attenuating p53 signaling. ATX generates LPA by cleaving LPC at the cell surface. LPA activates LPA2 that binds to Siva-1 and the complex becomes polyubiquitinated and degraded. This will prevent the depletion of Bcl-XL levels due to the degradation of Siva-1. LPA2 activation leads to the assembly of a ternary complex with TRIP6 and NHEF2. This complex enhances the activation of NFkB- and ERK1/2-mediated prosurvival signaling downstream of LPA2.