2. Academic Validation
  3. CCT020312 exerts anti-prostate cancer effect by inducing G1 cell cycle arrest, apoptosis and autophagy through activation of PERK/eIF2α/ATF4/CHOP signaling

CCT020312 exerts anti-prostate cancer effect by inducing G1 cell cycle arrest, apoptosis and autophagy through activation of PERK/eIF2α/ATF4/CHOP signaling

  • Biochem Pharmacol. 2024 Jan 28:221:116038. doi: 10.1016/j.bcp.2024.116038.
Duanfang Zhou 1,  Manjialan Yin 2,  Baoguo Kang 3,  Xiaoping Yu 2,  Hongfang Zeng 2,  Bo Chen 2,  Gang Wang 2,  Yi Song 2,  Xu Liu 2,  Qichen He 2,  Qiuya Wu 2,  Limei Zhang 2,  Lihong Wu 2,  Yuanli Wu 2,  Na Qu 2,  Xiaoli Li 4,  Weiying Zhou 5
Affiliations

Affiliations

  • 1 Department of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing 400016, China; Chongqing Key Laboratory of Drug Metabolism, Chongqing 400016, China; Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing 400016, China; Department of Pharmacy, Women and Children's Hospital of Chongqing Medical University, Chongqing 401147, China; Department of Pharmacy, Chongqing Health Center for Women and Children, Chongqing 401147, China.
  • 2 Department of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing 400016, China; Chongqing Key Laboratory of Drug Metabolism, Chongqing 400016, China; Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing 400016, China.
  • 3 Deputy Chief Physician, Department of Oncology, Liangjiang New District People's Hospital.
  • 4 Department of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing 400016, China; Chongqing Key Laboratory of Drug Metabolism, Chongqing 400016, China; Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing 400016, China. Electronic address: lixiaoli@cqmu.edu.cn.
  • 5 Department of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing 400016, China; Chongqing Key Laboratory of Drug Metabolism, Chongqing 400016, China; Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing 400016, China. Electronic address: wyzhou0118@cqmu.edu.cn.
PMID: 38286211 DOI: 10.1016/j.bcp.2024.116038
Abstract

PERK/eIF2α/ATF4/CHOP signaling pathway is one of three major branches of unfolded protein response (UPR) and has been implicated in tumor progression. CCT020312 is a selective PERK activator and may have a potential anti-tumor effect. Here we investigated the anti-prostate Cancer effect and its underlying mechanism of CCT020312. Our results showed that CCT020312 inhibited prostate Cancer cell viability by inducing cell cycle arrest, Apoptosis and Autophagy through activation of PERK/eIF2α/ATF4/CHOP signaling. CCT020312 treatment caused cell cycle arrest at G1 phase and increased the levels of cleaved-Caspase3, cleaved-PARP and Bax in prostate Cancer C4-2 and LNCaP cells. Moreover, CCT020312 increased LC3II/I, Atg12-Atg5 and Beclin1 levels and induced autophagosome formation. Furthermore, knockdown of CHOP reversed CCT020312-induced cell viability decrease, Apoptosis and Autophagy. Bafilomycin A1 reversed CCT020312-induced cell viability decrease but had no effect on CCT020312-induced CHOP activation in C4-2 and LNCaP cells. In vivo, CCT020312 suppressed tumor growth in C4-2 cells-derived xenograft mouse model, activated PERK pathway, and induced Autophagy and Apoptosis. Our study illustrates that CCT020312 exerts an anti-tumor effect in prostate Cancer via activating the PERK pathway, thus indicating that CCT020312 may be a potential drug for prostate Cancer.

Keywords

Apoptosis; Autophagy; CCT020312; PERK; Prostate cancer.

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