ER stress activates TAp73α to promote colon cancer cell apoptosis via the PERK-ATF4 pathway

Sun, Shengnan; Yi, Yong; Xiao, Zhi-Xiong Jim; Chen, Hu

doi:10.7150/jca.84170

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J Cancer 2023; 14(11):1946-1955. doi:10.7150/jca.84170 This issue Cite

Research Paper

ER stress activates TAp73α to promote colon cancer cell apoptosis via the PERK-ATF4 pathway

Shengnan Sun^1,3, Yong Yi¹, Zhi-Xiong Jim Xiao¹, Hu Chen^2✉

1. Center of Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, 610064, China.
2. Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu, 610500, China.
3. Research Center of Translational Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250013, China.

Citation:

Sun S, Yi Y, Xiao ZXJ, Chen H. ER stress activates TAp73α to promote colon cancer cell apoptosis via the PERK-ATF4 pathway. J Cancer 2023; 14(11):1946-1955. doi:10.7150/jca.84170. https://www.jcancer.org/v14p1946.htm

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Abstract

Colorectal cancer (CRC) is the fourth most diagnosed cancer worldwide. 43% of CRCs harbor p53 mutations. The tumor suppressor p53 induces cell growth arrest and/or apoptosis in response to stress, including endoplasmic reticulum (ER) stress. It has been documented that the p53 gene is mutated in more than 50% of human tumors and loses its tumor suppressor function, suggesting that ER stress-induced apoptosis might not rely on p53. In this study, we found that activation of ER stress promotes p53 null colon cancer cell apoptosis concomitant with an increased level of the TAp73α protein, a homologue of p53 in vitro and in vivo. Knockdown of TAp73α partially restores ER stress-induced apoptosis, indicating that ER stress stimulates apoptosis in a manner dependent on TAp73α, but not p53. Furthermore, we found that ER stress activates TAp73α mRNA and protein expression through PERK signalling, a branch of the unfolded protein response (UPR). Moreover, PERK promotes TAp73α expression by upregulating the expression of the transcription factor ATF4. ATF4 directly activates the transcription of TAp73α. Consistent with this finding, ATF4 knockdown inhibited PERK- or ER stress-induced TAp73α expression. Our findings reveal that ER stress activates TAp73α to promote colon cancer cell apoptosis via the PERK-ATF4 signalling. Therefore, prolonged ER stress or upregulation of TAp73α might be a therapeutic strategy for colon cancer.

Keywords: ER stress, Cell apoptosis, TAp73α, PERK, ATF4

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APA

Sun, S., Yi, Y., Xiao, Z.X.J., Chen, H. (2023). ER stress activates TAp73α to promote colon cancer cell apoptosis via the PERK-ATF4 pathway. Journal of Cancer, 14(11), 1946-1955. https://doi.org/10.7150/jca.84170.

ACS

Sun, S.; Yi, Y.; Xiao, Z.X.J.; Chen, H. ER stress activates TAp73α to promote colon cancer cell apoptosis via the PERK-ATF4 pathway. J. Cancer 2023, 14 (11), 1946-1955. DOI: 10.7150/jca.84170.

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CSE

Sun S, Yi Y, Xiao ZXJ, Chen H. 2023. ER stress activates TAp73α to promote colon cancer cell apoptosis via the PERK-ATF4 pathway. J Cancer. 14(11):1946-1955.

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