Acyl-coenzyme A: cholesterol acyltransferase inhibitor avasimibe suppresses tumorigenesis and induces G1-phase cell-cycle arrest by activating PPARγ signaling pathway in bladder cancer

Peng, Tianchen; Xiong, Kangping; He, Zhiwen; Cheng, Songtao; Chen, Siming; Chen, Song; Yang, Zhonghua; Xiang, Wan; Ju, Lingao; Zhang, Yi; Qian, Kaiyu; Xiao, Yu; Wang, Gang

doi:10.7150/jca.83856

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J Cancer 2024; 15(2):370-382. doi:10.7150/jca.83856 This issue Cite

Research Paper

Acyl-coenzyme A: cholesterol acyltransferase inhibitor avasimibe suppresses tumorigenesis and induces G1-phase cell-cycle arrest by activating PPARγ signaling pathway in bladder cancer

Tianchen Peng^1,#, Kangping Xiong^1,#, Zhiwen He^1,#, Songtao Cheng¹, Siming Chen¹, Song Chen¹, Zhonghua Yang¹, Wan Xiang², Lingao Ju^2,3,4, Yi Zhang^5,6, Kaiyu Qian^1,2, Yu Xiao^2,4,✉, Gang Wang^1,2,3✉

1. Department of Urology, Hubei Key Laboratory of Urological Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China.
2. Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China.
3. Human Genetic Resource Preservation Center of Hubei Province, Wuhan, China.
4. Laboratory of Precision Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.
5. Euler Technology, ZGC Life Sciences Park, Beijing, China.
6. Center for Quantitative Biology, School of Life Sciences, Peking University, Beijing, China.
^#These authors contributed equally to this work.

Citation:

Peng T, Xiong K, He Z, Cheng S, Chen S, Chen S, Yang Z, Xiang W, Ju L, Zhang Y, Qian K, Xiao Y, Wang G. Acyl-coenzyme A: cholesterol acyltransferase inhibitor avasimibe suppresses tumorigenesis and induces G1-phase cell-cycle arrest by activating PPARγ signaling pathway in bladder cancer. J Cancer 2024; 15(2):370-382. doi:10.7150/jca.83856. https://www.jcancer.org/v15p0370.htm

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Abstract

Reprogramming of energy metabolism is one of the most important characteristics of tumors. Bladder cancer (BLCA) cells contain higher levels of cholesterol content compared to normal cells, and acyl-coenzyme A (CoA): cholesterol acyltransferase-1 (ACAT1) plays a crucial role in the esterification of cholesterol. Avasimibe is a drug that has been used in the treatment of atherosclerosis, and it can effectively inhibit ACAT1. We observed that ACAT1 was significantly up-regulated in BLCA and positively correlated with tumor grade. By avasimibe administration, the proliferation and migration ability of BLCA cells were reduced, while the production of ROS was strongly increased, accompanied by the up-regulated expression of ROS metabolism-related proteins SOD2 and catalase. Furthermore, BLCA cell cycle was arrested at the G1 phase, accompanied by the downregulation of cell cycle-related proteins (CCNA1/2, CCND1, CDK2 and CDK4), while the PPARγ was found to be up-regulated at both transcriptional and protein levels after avasimibe treatment. Then we found that the PPARγ antagonist GW9662 could reverse the effect of avasimibe on the cell cycle. Moreover, xenograft and pulmonary metastasis models further demonstrated that avasimibe could inhibit tumor cell growth and metastasis in vivo. Taken together, our results for the first time revealed that avasimibe can inhibit BLCA progression and metastasis, and PPARγ signaling pathway may play a key role in regulation of cell cycle distribution induced by avasimibe.

Keywords: Bladder cancer (BLCA), acyl-coenzyme A: cholesterol acyltransferase-1 (ACAT1), avasimibe, PPARγ, cell cycle.

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APA

Peng, T., Xiong, K., He, Z., Cheng, S., Chen, S., Chen, S., Yang, Z., Xiang, W., Ju, L., Zhang, Y., Qian, K., Xiao, Y., Wang, G. (2024). Acyl-coenzyme A: cholesterol acyltransferase inhibitor avasimibe suppresses tumorigenesis and induces G1-phase cell-cycle arrest by activating PPARγ signaling pathway in bladder cancer. Journal of Cancer, 15(2), 370-382. https://doi.org/10.7150/jca.83856.

ACS

Peng, T.; Xiong, K.; He, Z.; Cheng, S.; Chen, S.; Chen, S.; Yang, Z.; Xiang, W.; Ju, L.; Zhang, Y.; Qian, K.; Xiao, Y.; Wang, G. Acyl-coenzyme A: cholesterol acyltransferase inhibitor avasimibe suppresses tumorigenesis and induces G1-phase cell-cycle arrest by activating PPARγ signaling pathway in bladder cancer. J. Cancer 2024, 15 (2), 370-382. DOI: 10.7150/jca.83856.

NLM

CSE

Peng T, Xiong K, He Z, Cheng S, Chen S, Chen S, Yang Z, Xiang W, Ju L, Zhang Y, Qian K, Xiao Y, Wang G. 2024. Acyl-coenzyme A: cholesterol acyltransferase inhibitor avasimibe suppresses tumorigenesis and induces G1-phase cell-cycle arrest by activating PPARγ signaling pathway in bladder cancer. J Cancer. 15(2):370-382.

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