Oleanolic Acid Induces Autophagy and Apoptosis via the AMPK-mTOR Signaling Pathway in Colon Cancer

Changxiao Hu; Yibo Cao; Ping Li; Xiaorong Tang; Minhui Yang; Shengliang Gu; Kai Xiong; Tian Li; Tianbao Xiao

doi:10.1155/2021/8281718

Oleanolic Acid Induces Autophagy and Apoptosis via the AMPK-mTOR Signaling Pathway in Colon Cancer

J Oncol. 2021 Jul 14:2021:8281718. doi: 10.1155/2021/8281718. eCollection 2021.

Authors

Changxiao Hu¹, Yibo Cao², Ping Li², Xiaorong Tang², Minhui Yang¹, Shengliang Gu¹, Kai Xiong¹, Tian Li³, Tianbao Xiao²

Affiliations

¹ College of Clinical Medicine, Guizhou University of Traditional Chinese Medicine, No. 71 Baoshan North Road, Guiyang 550001, China.
² Colorectal and Anal Surgery, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, No. 71 Baoshan North Road, Guiyang 550001, China.
³ Fourth Military Medical University, No. 169 Changle West Rd, Xi'an 710032, China.

Abstract

Aims: The purpose of this study was to explore the biological functions of the mTOR and AMPK signaling pathways in colon cancer (CC). The potential molecular mechanisms by which oleanolic acid (OA) induces autophagy and apoptosis were also investigated.

Methods: The biological functions of mTOR were analyzed by GeneCards, the Search Tool for the Retrieval of Interacting Genes (STRING), and the Database for Annotation, Visualization and Integrated Discovery (DAVID). Least absolute shrinkage and selection operator (LASSO) regression analysis was used to obtain prognostic and survival data of CC patients from the Gene Expression Omnibus (GEO) database. The effects of OA on the CC cell lines HCT-116 and SW-480 were analyzed by CCK-8, colony formation assay, and high-content system (HCS) array scan. The apoptosis rate of SW-480 and HCT-116 cells was detected by flow cytometry. The mRNA and protein expression levels in HCT-116 and SW-480 cells and NCM-460 normal colonic epithelial cells were detected by RT-PCR and Western blotting.

Results: mTOR was highly expressed in CC patients and acted as an oncogene. The AMPK signaling pathway mediated by mTOR predicted the poor prognosis of CC patients. OA effectively inhibited the proliferation and viability of CC cells. Furthermore, the apoptosis rate of CC cells was clearly increased following OA administration. Regarding the molecular mechanism of OA, the results indicated that mTOR and the antiapoptosis gene Bcl-2 were downregulated by OA. In addition, regulator genes of autophagy and apoptosis, including BAX, caspase-9, caspase-8, and caspase-3, were significantly upregulated by OA. Moreover, OA upregulated AMPK and its downstream proteins, including TSC2, BAX, Beclin 1, LC3B-II, and ULK1, to induce autophagy and apoptosis in CC cells.

Conclusion: The findings from this study demonstrate that OA could effectively inhibit the proliferation and viability of CC cells. The anti-CC activity of OA is closely related to the activation of the AMPK-mTOR signaling pathway. Activation of AMPK and inhibition of mTOR are involved in the induction of autophagy and apoptosis by OA. OA induced autophagy and apoptosis mainly in an AMPK activation-dependent manner in CC cells.