Inhibition of phosphoglycerate dehydrogenase induces ferroptosis and overcomes enzalutamide resistance in castration-resistant prostate cancer cells

Jinxiang Wang; Leli Zeng; Nisha Wu; Yanling Liang; Jie Jin; Mingming Fan; Xiaoju Lai; Zhe-Sheng Chen; Yihang Pan; Fangyin Zeng; Fan Deng

doi:10.1016/j.drup.2023.100985

Inhibition of phosphoglycerate dehydrogenase induces ferroptosis and overcomes enzalutamide resistance in castration-resistant prostate cancer cells

Drug Resist Updat. 2023 Sep:70:100985. doi: 10.1016/j.drup.2023.100985. Epub 2023 Jun 14.

Authors

Jinxiang Wang¹, Leli Zeng², Nisha Wu³, Yanling Liang⁴, Jie Jin³, Mingming Fan⁵, Xiaoju Lai⁵, Zhe-Sheng Chen⁶, Yihang Pan⁷, Fangyin Zeng⁸, Fan Deng⁹

Affiliations

¹ Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Precision Medicine Center, Department of Biobank, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China.
² Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Precision Medicine Center, Department of Biobank, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China.
³ Department of Clinical Laboratory, the Fifth Affiliated Hospital, Southern Medical University, Guangzhou, China.
⁴ Department of Clinical Laboratory, the Fifth Affiliated Hospital, Southern Medical University, Guangzhou, China; Department of Clinical Laboratory, Nanfang Hospital, Southern Medical University, Guangzhou, China.
⁵ Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
⁶ Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Jamaica, NY 11439, USA.
⁷ Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Precision Medicine Center, Department of Biobank, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China. Electronic address: panyih@mail.sysu.edu.cn.
⁸ Department of Clinical Laboratory, the Fifth Affiliated Hospital, Southern Medical University, Guangzhou, China. Electronic address: zengfy@126.com.
⁹ Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China. Electronic address: fandeng@smu.edu.cn.

PMID: 37423117
DOI: 10.1016/j.drup.2023.100985

Abstract

Phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in the first step of the serine synthesis pathway (SSP), is overexpressed in multiple types of cancers. The androgen receptor inhibitor enzalutamide (Enza) is the primary therapeutic drug for patients with castration-resistant prostate cancer (CRPC). However, most patients eventually develop resistance to Enza. The association of SSP with Enza resistance remains unclear. In this study, we found that high expression of PHGDH was associated with Enza resistance in CRPC cells. Moreover, increased expression of PHGDH led to ferroptosis resistance by maintaining redox homeostasis in Enza-resistant CRPC cells. Knockdown of PHGDH caused significant GSH reduction, induced lipid peroxides (LipROS) increase and significant cell death, resulting in inhibiting growth of Enza-resistant CRPC cells and sensitizing Enza-resistant CRPC cells to enzalutamide treatment both in vitro and in vivo. We also found that overexpression of PHGDH promoted cell growth and Enza resistance in CRPC cells. Furthermore, pharmacological inhibition of PHGDH by NCT-503 effectively inhibited cell growth, induced ferroptosis, and overcame enzalutamide resistance in Enza-resistant CRPC cells both in vitro and in vivo. Mechanically, NCT-503 triggered ferroptosis by decreasing GSH/GSSG levels and increasing LipROS production as well as suppressing SLC7A11 expression through activation of the p53 signaling pathway. Moreover, stimulating ferroptosis by ferroptosis inducers (FINs) or NCT-503 synergistically sensitized Enza-resistant CRPC cells to enzalutamide. The synergistic effects of NCT-503 and enzalutamide were verified in a xenograft nude mouse model. NCT-503 in combination with enzalutamide effectively restricted the growth of Enza-resistant CRPC xenografts in vivo. Overall, our study highlights the essential roles of increased PHGDH in mediating enzalutamide resistance in CRPC. Therefore, the combination of ferroptosis inducer and targeted inhibition of PHGDH could be a potential therapeutic strategy for overcoming enzalutamide resistance in CRPC.

Keywords: CRPC; Enzalutamide resistance; Ferroptosis; PHGDH; Redox homeostasis.