CC-115 Mediates GSDME-Dependent Pyroptosis in Lung Adenocarcinoma Through the Akt/Bax Pathway

Zhang, Ting; Liu, Ming-Quan; Xie, Guang-Su; Wu, Dong-Ming; Luo, Peng-Wei; Liu, Teng; Deng, Shi-Hua; Wang, Yuan-Yi; He, Shuang; Zhou, Ye; Zhou, Jin; Xu, Ying

doi:10.7150/jca.83175



International Journal of Biological Sciences

International Journal of Medical Sciences

Theranostics

Journal of Genomics

Nanotheranostics

Global reach, higher impact

Full Text | PDF

J Cancer 2023; 14(8):1350-1361. doi:10.7150/jca.83175 This issue Cite

Research Paper

CC-115 Mediates GSDME-Dependent Pyroptosis in Lung Adenocarcinoma Through the Akt/Bax Pathway

Ting Zhang^1†, Ming-Quan Liu^1†, Guang-Su Xie^2†, Dong-Ming Wu^1†, Peng-Wei Luo¹, Teng Liu¹, Shi-Hua Deng¹, Yuan-Yi Wang¹, Shuang He¹, Ye Zhou¹, Jin Zhou^3,✉, Ying Xu^1,2✉

1. School of Clinical Medicine & The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, China.
2. Xindu District People's Hospital of Chengdu, Chengdu 610500, China.
3. Sichuan Cancer Hospital and Institute, School of Medicine, University of Electronic Science and Technology, Sichuan 610042, China.
^† These authors contributed equally to this work

Citation:

Zhang T, Liu MQ, Xie GS, Wu DM, Luo PW, Liu T, Deng SH, Wang YY, He S, Zhou Y, Zhou J, Xu Y. CC-115 Mediates GSDME-Dependent Pyroptosis in Lung Adenocarcinoma Through the Akt/Bax Pathway. J Cancer 2023; 14(8):1350-1361. doi:10.7150/jca.83175. https://www.jcancer.org/v14p1350.htm

Other styles

Abstract

Chemotherapeutic agents remain the first-line treatment for solid tumors, including lung cancer, but chemotherapy resistance is hampering global efforts to treat this disease. CC-115 is a novel antitumoral compound used in phase I clinical trials. However, it is unclear whether CC-115 is effective against lung adenocarcinoma (LUAD). In the present study, we found that CC-115 induced lytic cell death in A549 and H1650 tumor cells via swelling of cells and formation of large bubbles on the plasma membrane that closely resembled those typical of pyroptosis, a type of programmed cell death linked to chemotherapy. We demonstrated that CC-115 exerts antitumor effects in LUAD through gasdermin E (GSDME)-mediated pyroptosis by acting as a dual inhibitor of DNA-PK and mTOR. CC-115 can inhibit Akt phosphorylation, impairing its inhibitory effect on Bax, thereby inducing pyroptosis via the Bax-mitochondrial intrinsic pathway. CC-115-induced pyroptosis was abrogated by treatment with the Akt activator SC79 or by depletion of Bax. Importantly, CC-115 significantly upregulated the expression of Bax and GSDME-N in a xenograft mouse model, with a reduction in tumor size. Our results revealed that CC-115 suppresses tumor growth by inducing GSDME-mediated pyroptosis through the Akt/Bax-mitochondrial intrinsic pathway, indicating CC-115 as a promising therapeutic agent for LUAD.

Keywords: Bax, pyroptosis, CC-115, GSDME, lung adenocarcinoma, chemotherapy

Citation styles

APA

Zhang, T., Liu, M.Q., Xie, G.S., Wu, D.M., Luo, P.W., Liu, T., Deng, S.H., Wang, Y.Y., He, S., Zhou, Y., Zhou, J., Xu, Y. (2023). CC-115 Mediates GSDME-Dependent Pyroptosis in Lung Adenocarcinoma Through the Akt/Bax Pathway. Journal of Cancer, 14(8), 1350-1361. https://doi.org/10.7150/jca.83175.

ACS

Zhang, T.; Liu, M.Q.; Xie, G.S.; Wu, D.M.; Luo, P.W.; Liu, T.; Deng, S.H.; Wang, Y.Y.; He, S.; Zhou, Y.; Zhou, J.; Xu, Y. CC-115 Mediates GSDME-Dependent Pyroptosis in Lung Adenocarcinoma Through the Akt/Bax Pathway. J. Cancer 2023, 14 (8), 1350-1361. DOI: 10.7150/jca.83175.

NLM

CSE

Zhang T, Liu MQ, Xie GS, Wu DM, Luo PW, Liu T, Deng SH, Wang YY, He S, Zhou Y, Zhou J, Xu Y. 2023. CC-115 Mediates GSDME-Dependent Pyroptosis in Lung Adenocarcinoma Through the Akt/Bax Pathway. J Cancer. 14(8):1350-1361.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.