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

Oncogene volume 39, pages 6757–6775 (2020)Cite this article

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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.

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Fig. 1: LIFR upregulation is involved in the NE differentiation of prostate cancer.
Fig. 2: ADT upregulates the LIFR, which promotes the NE differentiation of prostate cancer.
Fig. 3: Activated EGFR pathway enhances LIFR expression.
Fig. 4: ADT-induced SUCLG2 is regulated by LIF–LIFR–STAT3 signaling.
Fig. 5: Activation of LIF–LIFR signaling promotes SUCLG2-driven mtDNA content and NDPK enzymatic activity in prostate cancer cells.
Fig. 6: Targeting SUCLG2 reduces the tumor growth of AR-negative or ADT-resistant prostate cancer cells.
Fig. 7: Induced SUCLG2 is positively associated with prostate cancer progression.

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Acknowledgements

This work was jointly supported by grants from the Ministry of Science and Technology of Taiwan (MOST108-2320-B-038-047) to WYC, (MOST 109-2314-B-038-105) to YCW, and (MOST109-2326-B-038-001-MY3) to YNL, Taipei Medical University—Wan Fang Hospital (109TMU-WFH-01) to WYC, and the National Health Research Institute of Taiwan (NHRI-EX109-10702BI) to YNL.

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  1. These authors contributed equally: Shian-Ren Lin, Yu-Ching Wen

Authors and Affiliations

  1. Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan

    Shian-Ren Lin, Kuo-Ching Jiang, Wei-Hao Chen, Ntlotlang Mokgautsi & Yen-Nien Liu

  2. Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

    Yu-Ching Wen

  3. Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

    Yu-Ching Wen

  4. Institute of Information System and Applications, National Tsing Hua University, Hsinchu, Taiwan

    Hsiu-Lien Yeh

  5. Department of Pathology, Duke University Medical Center, Durham, NC, USA

    Jiaoti Huang & Yen-Nien Liu

  6. Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

    Wei-Yu Chen

  7. Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

    Wei-Yu Chen

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Contributions

WYC and YNL designed the experiments and supervised the project. SRL, HLY, KCJ, and WHC performed the experiments. YCW, WYC, and JH provided the human prostate cancer samples. WYC performed the histomorphometric analysis. HLY constructed the databases and performed the statistical and computational analyses. SRL, YCW, WYC, and YNL wrote, reviewed, and/or revised the manuscript. All authors analyzed and interpreted the data.

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Correspondence to Wei-Yu Chen or Yen-Nien Liu.

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Tissue samples were used in accordance with the Declaration of Helsinki and U.S. Common Rule, and their use was approved by the Taipei Medical University—Joint Institutional Review Board (approval no. N201711067) and the Duke University School of Medicine—Institutional Review Board (protocol ID, Pro00070193).

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Lin, SR., Wen, YC., Yeh, HL. et al. EGFR-upregulated LIFR promotes SUCLG2-dependent castration resistance and neuroendocrine differentiation of prostate cancer. Oncogene 39, 6757–6775 (2020). https://doi.org/10.1038/s41388-020-01468-9

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