Lysophosphatidic acid induces tumor necrosis factor‐alpha to regulate a pro‐inflammatory cytokine network in ovarian cancer

Abstract

Epithelial ovarian carcinoma tissues express high levels of tumor necrosis factor‐alpha (TNF‐α) and other inflammatory cytokines. The underlying mechanism leading to the abnormal TNF‐α expression in ovarian cancer remains poorly understood. In the current study, we demonstrated that lysophosphatidic acid (LPA), a lipid mediator present in ascites of ovarian cancer patients, induced expression of TNF‐α mRNA and release of TNF‐α protein in ovarian cancer cells. LPA also induced expression of interleukin‐1β (IL‐1β) mRNA but no significant increase in IL‐1β protein was detected. LPA enhanced TNF‐α mRNA through NF‐κB‐mediated transcriptional activation. Inactivation of ADAM17, a disintegrin and metalloproteinase, with a specific inhibitor TMI‐1 or by shRNA knockdown prevented ovarian cancer cells from releasing TNF‐α protein in response to LPA, indicating that LPA‐mediated TNF‐α production relies on both transcriptional upregulations of the TNF‐α gene and the activity of ADAM17, the membrane‐associated TNF‐α‐converting enzyme. Like many other biological responses to LPA, induction of TNF‐α by LPA also depended on the transactivation of the epidermal growth factor receptor (EGFR). Interestingly, our results revealed that ADAM17 was also the shedding protease responsible for the transactivation of EGFR by LPA in ovarian cancer cells. To explore the biological outcomes of LPA‐induced TNF‐α, we examined the effects of a TNF‐α neutralizing antibody and recombinant TNF‐α soluble receptor on LPA‐stimulated expression of pro‐tumorigenic cytokines and chemokines overexpressed in ovarian cancer. Blockade of TNF‐α signaling significantly reduced the production of IL‐8, IL‐6, and CXCL1, suggesting a hierarchy of mechanisms contributing to the robust expression of the inflammatory mediators in response to LPA in ovarian cancer cells. In contrast, TNF‐α inhibition did not affect LPA‐dependent cell proliferation. Taken together, our results establish that the bioactive lipid LPA drives the expression of TNF‐α to regulate an inflammatory network in ovarian cancer.

Pathway-level mutation analysis in primary high-grade serous ovarian cancer and matched brain metastases

“…The level of LPA in plasma and ascites is increased even in the early stages of OC and has been considered a potential diagnostic marker in OC 46 . LPA stimulates the proliferation, migration, and invasion of OC cells through the regulation of several factors, i.e., vascular endothelial growth factor, tumor-necrosis factor α, and CXC chemokine ligand 47 . In the central nervous system, LPA signaling influences numerous processes, including the proliferation of neural precursor cells, neural and glial development, proper cell migration, and cell survival 48 .…”

Resveratrol Contrasts LPA-Induced Ovarian Cancer Cell Migration and Platinum Resistance by Rescuing Hedgehog-Mediated Autophagy

“…Lysophosphatidic acid (LPA), a lipid growth factor highly secreted in the ovarian tumor microenvironment [13], exerts several pro-tumorigenic activities such as (i) reprogramming toward a glycolytic shift that associates with the pheno-conversion of ovarian normal fibroblasts into cancer-associated fibroblasts (CAFs) [14] and with the enhanced proliferation of ovarian cancer cells [15], (ii) upregulating the oncogenic/growth-promoting transcriptome [16,17], (iii) promoting EMT and invasiveness [18,19], (iv) stimulating the secretion of pro-inflammatory and angiogenic factors (such as TNF-α, IL-6, IL-8, VEGF, etc.) [20,21], and (v) promoting therapy resistance either by supporting an immunosuppressive phenotype or by protecting tumor cells from apoptosis [21]. Additionally, it has been reported that LPA inhibits autophagy in prostate cancer cells [22,23].…”

Influence of the autotaxin-lysophosphatidic acid axis on cellular function and cytokine expression in different breast cancer cell lines

“…Further, TNF-alpha enhances ATX production in the adjacent adipose tissue 19 . A recent study showed that LPA induces secretion of TNF-alpha in ovarian cancer cells and thus, adjusts an inflammatory network in ovarian cancer 52 . However, to our knowledge, no prior study has revealed an LPA-induced TNF-alpha secretion in breast cancer cells.…”

“…Whereas we observed an enhanced release of TNF-alpha in MDA-MB-468 cells, we found a decreased secretion of TNF-alpha in MDA-MB-231 cells after incubation with LPA. Wang et al established the involvement of LPAR2 in the mediation of TNF-alpha induction and reported a minor or even inhibitory role of LPAR3 in TNF-alpha release in ovarian cancer cell lines 52 . LPA-induced secretion of TNF-alpha in MDA-MB-468 and the corresponding LPAR expression profile of this cell line in the present study support the proposed involvement of LPAR2 in TNF-alpha production.…”