EGFR-upregulated LIFR promotes SUCLG2-dependent castration resistance and neuroendocrine differentiation of prostate cancer.

Abstract

Neuroendocrine (NE) differentiation is a well-recognized phenotypic change of prostate cancer after androgen deprivation therapy (ADT), and it ultimately develops into an aggressive subset of this disease. However, the contribution of signaling pathways that lead to metabolic disorders and NE differentiation of prostate cancer remains unclear. In this study, we identified that ADT induced upregulation of the succinate-CoA ligase GDP-forming beta subunit (SUCLG2), which regulates succinate metabolism and NE differentiation of prostate cancer. We demonstrated a connection that upregulation of epidermal growth factor receptor (EGFR)-leukemia inhibitory factor receptor (LIFR) signaling induced SUCLG2 expression in prostate cancer cells. The LIFR is upregulated by nuclear EGFR, which acts as a transcriptional regulator, directly binds to the LIFR promoter, and drives NE differentiation and glycolysis of prostate cancer. LIFR upregulation is associated with SUCLG2, which increased succinate synthesis and enzymatic activities of mitochondrial nucleoside diphosphate kinase (NDPK) in prostate cancer cells. Knockdown of SUCLG2 suppressed NE differentiation in cultured cells and reduced prostate tumor growth in a xenograft model. Analysis of prostate tissue samples showed increased intensity of nuclear EGFR associated with the LIFR and SUCLG2 in castration-resistant prostate cancer tumors. Our study provides a mechanism whereby ADT upregulates EGFR-LIFR signaling that activates SUCLG2, which subsequently stimulates the metabolic changes associated with NE differentiation and aggressive prostate cancer phenotype.

• Authors: Shian-Ren Lin, Yu-Ching Wen, Hsiu-Lien Yeh, Kuo-Ching Jiang, Wei-Hao Chen, Ntlotlang Mokgautsi, Jiaoti Huang, Wei-Yu Chen, Yen-Nien Liu
• Journal: Oncogene (Oncogene) Vol. 39 Issue 44 Pg. 6757-6775 (10 2020) ISSN: 1476-5594 [Electronic] England
• PMID: 32963351 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AR protein, human
• Androgen Antagonists
• LIFR protein, human
• Leukemia Inhibitory Factor Receptor alpha Subunit
• Receptors, Androgen
• EGFR protein, human
• ErbB Receptors
• SUCLG2 protein, human
• Succinate-CoA Ligases

Topics

• Androgen Antagonists (pharmacology, therapeutic use)
• Animals
• Cell Differentiation (drug effects, genetics)
• Cell Line, Tumor
• Cell Nucleus (pathology)
• Cell Transdifferentiation (drug effects, genetics)
• ErbB Receptors (metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Knockdown Techniques
• Glycolysis (drug effects, genetics)
• Humans
• Leukemia Inhibitory Factor Receptor alpha Subunit (genetics, metabolism)
• Male
• Mice
• Neuroendocrine Tumors (drug therapy, genetics, pathology)
• Promoter Regions, Genetic
• Prostate (drug effects, pathology)
• Prostatic Neoplasms, Castration-Resistant (drug therapy, genetics, pathology)
• Receptors, Androgen (metabolism)
• Signal Transduction (drug effects, genetics)
• Succinate-CoA Ligases (genetics, metabolism)
• Up-Regulation (drug effects)
• Xenograft Model Antitumor Assays