Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
Role of the autotaxin–lysophosphatidate axis in cancer resistance to chemotherapy and radiotherapy☆
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 (Ca2 + 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 LPA1/2/3/4 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.
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2020, Bioorganic ChemistryCitation 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].
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This article is part of a Special Issue entitled Advances in Lysophospholipid Research.