Ovarian Cancer Cell-derived Lysophosphatidic Acid Induces Glycolytic Shift and Cancer-associated Fibroblast-phenotype in Normal and Peritumoral Fibroblasts

Overview

Journal Cancer Lett

Specialty Oncology

Date 2018 Dec 4

PMID 30503552

Citations 64

Authors

Rangasudhagar Radhakrishnan

Ji Hee Ha

Muralidharan Jayaraman

Jinsong Liu

Katherine M Moxley

Ciro Isidoro

Anil K Sood

Yong Sang Song

Danny N Dhanasekaran

Affiliations

Soon will be listed here.

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.

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