Title

STAT3 Promotes Ovarian Cancer Growth and Chemoresistance by Modulating Its Energy Metabolism

Document Type

Conference Proceeding

Publication Date

2019

Publication Title

Gynecol Oncol

Abstract

Objective: STAT3 (signal transducer and activator of transcription 3) is associated with tumor progression, metastasis, and chemoresistance in ovarian cancer. High STAT3 expression is a predictor of poor prognosis in ovarian cancer patients. Recently STAT3 has been shown to modulate mitochondrial function to promote carcinogenesis. Our aim was to investigate whether mitochondrial STAT3 can modulate cellular metabolism of ovarian cancer cells and promote oncogenic abilities. Method: STAT3-stable clones were generated in A2780 ovarian cancer cells, along with empty vector (pcDNA) clones. Proliferation was estimated by MTT and colony formation assays. Various clones were grown as xenografts in nude mice and treated with STAT3 inhibitor (STATTIC) via intraperitoneal injections. Seahorse XF Extracellular Flux analyzer was used to measure the bioenergetic phenotype by real-time measurements of glycolysis and mitochondrial oxidation using extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) as outputs, respectively. Results: Induced expression of STAT3 in A2780 ovarian cancer cells caused increased proliferation (P < 0.01), colony formation (P < 0.001), and chemoresistance (P < 0.01) in vitro, and large ovarian tumors (P < 0.01) in vivo compared to parental/pcDNA controls. Bioenergetic profiling showed higher OCR and ECAR in clones expressing STAT3 (P < 0.01), suggesting their “metabolically active" phenotype compared to the metabolically less active phenotype of parental/pcDNA clones. STATTIC inhibited both nuclear and mitochondrial STAT3 and inhibited the proliferation of STAT3 over-expressing A2780 cells in vitro (P < 0.01) and in vivo (P < 0.01), reduced their chemoresistance (P < 0.05), and reversed their metabolically active state. In contrast, a selective inhibitor of nuclear STAT3, cryptotanshinone, was relatively less effective in reducing the chemoresistance and metabolic changes. Ascites-driven ovarian cancer cells from patients with chemoresistant ovarian cancer showed increased expression of mitochondrial-STAT3 compared to nuclear-STAT3. Conclusion: Mitochondrial-STAT3 can induce metabolic changes in ovarian cancer cells and enhance their cellular fitness by promoting chemoresistance.

Volume

154

First Page

94

Last Page

95

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