RKI-1447 suppresses colorectal carcinoma cell growth via disrupting cellular bioenergetics and mitochondrial dynamics

作者

Li, LY; Chen, Q; Yu, YJ; Chen, H; Lu, MD; Huang, YP; Li, PH; Chang, H

作者单位

[Li, Liyi; Chen, Hui; Lu, Mingdong; Huang, Yingpeng; Li, Pihong; Chang, Hong] Shandong Univ, Shandong Prov Hosp, Gen Surg Dept, Jinan, Shandong, Peoples R China; [Li, Liyi; Yu, Yaojun] Wenzhou Med Univ, Affiliated Hosp 2, Gen Surg Dept, Wenzhou, Zhejiang, Peoples R China; [Chen, Qin] Wenzhou Med Univ, Affiliated Hosp 1, Dept Intens Care, Wenzhou, Peoples R China

摘要

Accumulated evidence suggested the importance of the Rho/Rho-kinase (ROCK) signaling pathway in cancer proliferation and invasion. However, its role in colorectal carcinoma (CRC) is not well understood. This study evaluated the effect of ROCK signaling pathway on CRC behavior on the basis of a novel Rho/ROCK inhibitor RKI-1447. Here, we found RKI-1447 could drastically suppress HCT-8 and HCT-116 cell growth and promoted apoptosis. Our in vitro data indicated suppressed cytoskeletal dynamics induced by RKI-1447 inhibition on mitochondrial respiration, which was evidenced by basal and maximal respiration rates, and ATP production. Simultaneously, cellular basal and maximal glycolytic rates, and glycolytic capacity were also reduced in response to RKI-1447. Moreover, RKI-1447 caused excessive reactive oxygen species generation and membrane depolarization as well as activated ER-stress. We also demonstrated CHOP is essential for RKI-1447 induced cell apoptosis. Finally, we proved inhibition of ROCK by RKI-1447 could effectively inhibit CRC growth in vivo. Taken together, this study demonstrated that inhibition of ROCK signaling pathway by RKI-1447 could suppress CRC via cytoskeleton associated mitochondrial dysfunction and cellular bioenergetics disruption. Our data suggest RKI-1447 may be an attractive antitumor drug candidate for the treatment of CRC.

关键词

KINASE ROK-ALPHA; CITRON KINASE; CANCER-CELLS; APOPTOSIS; RHO; PROTEIN; ACTIVATION; INVASION; REORGANIZATION; METASTASIS

基本信息

所属机构:

归属医师: 常宏

PMID：31237697

UT：000488990600021

刊名:JOURNAL OF CELLULAR PHYSIOLOGY

年，卷(期):2020年235卷1期

页码：254-266

DOI：10.1002/jcp.28965

附件： other

收录: SCIE