Abstract 725: LIFR promotes SUCLG2-dependent castration resistance and neuroendocrine differentiation of prostate cancer

Abstract

Abstract Neuroendocrine (NE) differentiation is a well-recognized phenotypic change of prostate cancer after androgen-deprivation therapy (ADT) that ultimately develops an aggressive subtype. An increasing number of patients with NE histologic type prostate cancer present with metabolic genes disorder. However, the metabolic pathways that influence the malignant transformation and the NE differentiation of prostate cancer remain unclear. In this study, we found that ADT induced the upregulation of leukemia inhibitory factor receptor (LIFR), which contributes to the expression of succinate-CoA ligase GDP-forming beta subunit (SUCLG2), thus activating metabolic reprogramming to enable NE differentiation and increase aggressiveness. Activated LIF-LIFR-STAT3 axis stimulates SUCLG2 expression, subsequently upregulating glucose metabolism and the NE differentiation of prostate cancer. SUCLG2 knockdown markedly reduced mitochondrial DNA content and inhibited the enzymatic activity of succinyl-CoA synthetase and nucleoside diphosphate kinase (NDPK) in prostate cancer cells. SUCLG2 overexpression promoted androgen-independent proliferation; however, SUCLG2 knockdown suppressed NE differentiation and the ADT resistance of prostate cancer cells. Analysis of prostate tissue samples showed an increased intensity of LIFR associated with SUCLG2 in castration-resistant prostate cancer tumors. Our study identifies SUCLG2 as a potential prognostic marker of ADT-resistant prostate cancer and suggests it could be a target for prostate cancer treatment. Citation Format: Hsiu-Lien Yeh, Shian-Ren Lin, Kuo-Ching Jiang, Wei-Hao Chen, Yen-Nien Liu. LIFR promotes SUCLG2-dependent castration resistance and neuroendocrine differentiation of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 725.