期刊
CANCER LETTERS
卷 442, 期 -, 页码 464-474出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2018.11.023
关键词
Ovarian-cancer; Cancer-associated fibroblasts; Lysophosphatidic acid; Hypoxia-inducible factor 1; HIF1; Glycolysis
类别
资金
- National Institutes of Health [GM103639]
- National Research Foundation of Korea BK Program [2009-0093820]
- Stephenson Cancer Center, OUHSC, Oklahoma City, OK
- Mary K. Chapman Foundation
- National Institute of General Medical Sciences of the National Institutes of Health [P20 GM103639]
- National Cancer Institute of the National Institutes of Health [P30CA225520]
- National Research Foundation of Korea BK21 Plus Program [5256-20140100]
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 MRCS 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 (MRCS) 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 HIF1 alpha-levels and the silencing of HIF1 alpha 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-HIF1 alpha 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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