AT7867 Inhibits the Growth of Colorectal Cancer Stem-Like Cells and Stemness by Regulating the Stem Cell Maintenance Factor Ascl2 and Akt Signaling

Yuchen Li; Yun Yuan; Luyao Yang; Hongqing Chen; Xufan Zhang; Tian Wen; Wenhao Liao; Maoyuan Zhao; Ziyi Zhao; Qiongying Hu

doi:10.1155/2023/4199052

AT7867 Inhibits the Growth of Colorectal Cancer Stem-Like Cells and Stemness by Regulating the Stem Cell Maintenance Factor Ascl2 and Akt Signaling

Stem Cells Int. 2023 Feb 14:2023:4199052. doi: 10.1155/2023/4199052. eCollection 2023.

Authors

Yuchen Li^{1

2}, Yun Yuan¹, Luyao Yang^{1

2}, Hongqing Chen^{1

2}, Xufan Zhang^{1

2}, Tian Wen^{1

2}, Wenhao Liao³, Maoyuan Zhao³, Ziyi Zhao^{3

4}, Qiongying Hu¹

Affiliations

¹ Department of Laboratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.
² College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
³ Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.
⁴ Traditional Chinese Medicine Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Chengdu, China.

Abstract

Cancer stem cells (CSCs) are the core factors leading to recurrence, insensitivity to radiotherapy and chemotherapy, and immunotherapy resistance in patients with colorectal cancer. AT7867, a potent oral AKT inhibitor, was found to have antitumor activity in colorectal cancer; however, the effect on colorectal cancer stem cells is still unclear. This study was conducted to clarify the molecular mechanism underlying the CSC growth inhibitory effects of AT7867. We cultured colorectal cancer cells (CRCs) in a serum-free medium and enriched colorectal cancer stem cells. Subsequently, the effects of AT7867 on CSCs were analyzed by CCK-8, colony formation, flow cytometry, and immunofluorescence assays. The results indicated that AT7867 induces G2/M phase arrest and cell apoptosis in cancer stem cells. Subsequently, we identified Ascl2 as the main gene affecting the stemness of colorectal cancer in AT7867 by RNA sequencing. The current study showed that Ascl2 is involved in the metastasis, invasion, and proliferation of CRCs. The next experiments demonstrated that overexpression of Ascl2 did affect the therapeutic effect of AT7867 on CRC stemness. Furthermore, compared with other Akt inhibitors, AT7867 could promote the differentiation of colorectal cancer stem cells. Thus, AT7867 might be a potential antitumor drug candidate to treat CRC by targeting CSCs.