Isoalantolactone Induces Cell Cycle Arrest, Apoptosis and Autophagy in Colorectal Cancer Cells

Junkui Li; Peili Zhu; Yifei Chen; Shiqing Zhang; Zhu Zhang; Zhang Zhang; Ying Wang; Xiaoli Jiang; Kaili Lin; Wei Wu; Zhixian Mo; Stephen Cho Wing Sze; Ken Kin Lam Yung

doi:10.3389/fphar.2022.903599

Isoalantolactone Induces Cell Cycle Arrest, Apoptosis and Autophagy in Colorectal Cancer Cells

Front Pharmacol. 2022 May 12:13:903599. doi: 10.3389/fphar.2022.903599. eCollection 2022.

Authors

Junkui Li^{1

2}, Peili Zhu^{1

2}, Yifei Chen^{3

4}, Shiqing Zhang^{2

5}, Zhu Zhang^{1

2}, Zhang Zhang^{1

2}, Ying Wang^{1

2}, Xiaoli Jiang^{1

2}, Kaili Lin^{2

6}, Wei Wu⁴, Zhixian Mo³, Stephen Cho Wing Sze^{1

2}, Ken Kin Lam Yung^{1

2}

Affiliations

¹ Department of Biology, Hong Kong Baptist University (HKBU), Kowloon Tong, China.
² Golden Meditech Center for NeuroRegeneration Sciences (GMCNS), HKBU, Kowloon Tong, China.
³ School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.
⁴ School of Pharmacy, Guilin Medical University, Guilin, China.
⁵ JNU-HKUST Joint Laboratory for Neuroscience and Innovative Drug Research, College of Pharmacy, Jinan University, Guangzhou, China.
⁶ School of Public Health, Guangzhou Medical University, Guangzhou, China.

Abstract

Colorectal cancer (CRC) is an aggressive cancer. Isoalantolactone (IATL) has been reported to exert cytotoxicity against various cancer cells, but not CRC. In this study, we explored the anti-CRC effects and mechanism of action of IATL in vitro and in vivo. Our results demonstrated that IATL inhibited proliferation by inducing G0/G1 phase cell cycle arrest, apoptosis and autophagy in CRC cells. Repression of autophagy with autophagy inhibitors chloroquine (CQ) and Bafilomycin A1 (Baf-A1) enhanced the anti-CRC effects of IATL, suggesting that IATL induces cytoprotective autophagy in CRC cells. Mechanistic studies revealed that IATL lowered protein levels of phospho-AKT (Ser473), phospho-mTOR (Ser2448), phospho-70S6K (Thr421/Ser424) in CRC cells. Inhibition of AKT and mTOR activities using LY294002 and rapamycin, respectively, potentiated the inductive effects of IATL on autophagy and cell death. In vivo studies showed that IATL suppressed HCT116 tumor growth without affecting the body weight of mice. In consistent with the in vitro results, IATL lowered protein levels of Bcl-2, Bcl-XL, phospho-AKT (Ser473), phospho-mTOR (Ser2448), and phsopho-70S6K (Thr421/Ser424), whereas upregulated protein levels of cleaved-PARP and LC3B-II in HCT116 tumors. Collectively, our results demonstrated that in addition to inhibiting proliferation, inducing G0/G1-phase cell cycle arrest and apoptosis, IATL initiates cytoprotective autophagy in CRC cells by inhibiting the AKT/mTOR signaling pathway. These findings provide an experimental basis for the evaluation of IATL as a novel medication for CRC treatment.

Keywords: AKT/mTOR signaling; apoptosis; autophagy; cell cycle arrest; colorectal cancer; isoalantolactone.