DOI: 10.1101/472613Nov 17, 2018Paper

Targeting IDH1 as a pro-senescent therapy in high-grade serous ovarian cancer

BioRxiv : the Preprint Server for Biology
Erika S DahlKatherine M Aird

Abstract

Epithelial ovarian cancer (EOC) is the deadliest gynecological cancer. High-grade serous carcinoma (HGSC) is the most frequently diagnosed and lethal histosubtype of EOC. A significant proportion of HGSC patients relapse with chemoresistant disease. Therefore, there is an urgent need for novel therapeutic strategies for HGSC. Metabolic reprogramming is a hallmark of cancer cells, and targeting metabolism for cancer therapy may be beneficial. Here we found that in comparison to normal fallopian tube epithelial cells, HGSC cells preferentially utilize glucose in the TCA cycle and not for aerobic glycolysis. This correlated with universally increased TCA cycle enzyme expression in HGSC cells under adherent conditions. To further differentiate the necessity of TCA cycle enzymes in ovarian cancer progression, we found that only wildtype isocitrate dehydrogenase I (IDH1) is both significantly increased in HGSC cells in spheroid conditions and is associated with reduced progression-free survival. IDH1 protein expression is also increased in primary HGSC patient tumors. Pharmacological inhibition or knockdown of IDH1 decreased proliferation of multiple HGSC cell lines by inducing senescence. Mechanistically, suppression of IDH1 increas...Continue Reading

Related Concepts

Epithelial Cells
Glycolysis
Histones
Metabolism
Neoplasms
Ovarian Carcinoma
Serous Membrane
Proliferating Cell Nuclear Antigen
Isocitrate Dehydrogenase-I
Cystadenocarcinoma, Serous

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