C16, a PKR inhibitor, suppresses cell proliferation by regulating the cell cycle via p21 in colorectal cancer

• Published in: Scientific reports Vol. 14; no. 1; p. 9029
• Main Authors: Hashimoto, Yu, Tokumoto, Yoshio, Watanabe, Takao, Ogi, Yusuke, Sugishita, Hiroki, Akita, Satoshi, Niida, Kazuki, Hayashi, Mirai, Okada, Masaya, Shiraishi, Kana, Tange, Kazuhiro, Tomida, Hideomi, Yamamoto, Yasunori, Takeshita, Eiji, Ikeda, Yoshio, Oshikiri, Taro, Hiasa, Yoichi
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 19.04.2024; Nature Portfolio
• Subjects: Antitumor activity; Antitumour agents; Apoptosis; C16; Cancer; Cell Cycle; Cell Division - drug effects; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - drug effects; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Double-stranded RNA; eIF-2 kinase; eIF-2 Kinase - antagonists & inhibitors; Flow cytometry; Gene expression; Gene Expression Regulation, Neoplastic; GTP-binding protein; Humans; Immunohistochemistry; Indoles - pharmacology; Inhibitors; Kinases; Proliferation; Protein Kinase Inhibitors - pharmacology; Protein kinase R; Proteins; Thiazoles - pharmacology; Tumor growth; C16; Tumor growth; Cell cycle; Colorectal cancer
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-59671-7

Double-stranded RNA-activated protein kinase R (PKR) is highly expressed in colorectal cancer (CRC). However, the role of PKR in CRC remains unclear. The aim of this study was to clarify whether C16 (a PKR inhibitor) exhibits antitumor effects and to identify its target pathway in CRC. We evaluated the effects of C16 on CRC cell lines using the MTS assay. Enrichment analysis was performed to identify the target pathway of C16. The cell cycle was analyzed using flow cytometry. Finally, we used immunohistochemistry to examine human CRC specimens. C16 suppressed the proliferation of CRC cells. Gene Ontology (GO) analysis revealed that the cell cycle-related GO category was substantially enriched in CRC cells treated with C16. C16 treatment resulted in G1 arrest and increased p21 protein and mRNA expression. Moreover, p21 expression was associated with CRC development as observed using immunohistochemical analysis of human CRC tissues. C16 upregulates p21 expression in CRC cells to regulate cell cycle and suppress tumor growth. Thus, PKR inhibitors may serve as a new treatment option for patients with CRC.