Ovarian cancer cell-derived lysophosphatidic acid induces glycolytic shift and cancer-associated fibroblast-phenotype in normal and peritumoral fibroblasts.

Abstract

Cancer-associated fibroblasts (CAFs) play a critical role in cancer progression, metastasis, and therapy resistance. Molecular events that confer CAF-phenotype to predecessor-cells are not fully understood. We demonstrate here that the ovarian cancer cell-conditioned medium (OCC-CM) induces CAF-phenotype in MRC5 lung-fibroblasts and it can be mimicked by LPA. While OCC-CM and LPA stimulated the expression of cellular CAF-markers by 3-days, they induced aerobic glycolysis, a metabolic marker for CAF, by 6 hrs. OCC-CM/LPA-induced glycolysis in lung (MRC5) as well as ovarian fibroblasts (NOF151) was inhibited by the LPA-receptor antagonist, Ki16425. Ovarian cancer patient-derived ascitic fluid-induced aerobic glycolysis in both NFs and Ovarian CAFs and it was inhibited by Ki16425. Further analysis indicated that LPA upregulated HIF1α-levels and the silencing of HIF1α attenuated LPA-induced glycolysis in both NOFs and CAFs. These results establish LPA-induced glycolytic-shift as the earliest, potentially priming event, in NF to CAF-transition. These findings also identify a role for LPA-LPAR-HIF1α signaling-hub in the maintenance of the glycolytic-phenotype in CAFs. Our results provide evidence that targeted inhibition of LPA-mediated metabolic reprogramming in CAFs may represent an adjuvant therapy in ovarian cancer.

• Authors: Rangasudhagar Radhakrishnan, Ji Hee Ha, Muralidharan Jayaraman, Jinsong Liu, Katherine M Moxley, Ciro Isidoro, Anil K Sood, Yong Sang Song, Danny N Dhanasekaran
• Journal: Cancer letters (Cancer Lett) Vol. 442 Pg. 464-474 (02 01 2019) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 30503552 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Culture Media, Conditioned
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Lysophospholipids
• Receptors, Lysophosphatidic Acid
• lysophosphatidic acid

Topics

• Ascitic Fluid (metabolism)
• Cancer-Associated Fibroblasts (metabolism, pathology)
• Cell Differentiation
• Cell Line, Tumor
• Culture Media, Conditioned
• Female
• Glycolysis
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Lysophospholipids (metabolism)
• Ovarian Neoplasms (metabolism, pathology)
• Paracrine Communication
• Phenotype
• Receptors, Lysophosphatidic Acid (metabolism)
• Signal Transduction