14-3-3zeta is involved in the anticancer effect of metformin in colorectal carcinoma.

Abstract

Metformin is a promising drug for cancer prevention and treatment, especially in the diabetic population. We aimed to test whether 14-3-3zeta affects the anticancer effect of metformin on colorectal carcinoma (CRC). In this study, we confirmed that higher 14-3-3zeta expression was found in CRC tissues than in pericarcinoma tissues, and in CRC tissue of patients with diabetes than in those without diabetes. A knockdown of 14-3-3zeta inhibited CRC proliferation and promoted apoptosis in vitro and in vivo. Then, we created stable cell lines with under-expressed 14-3-3zeta from SW480 and HCT15 cells after infection by a lentiviral vector carrying short hairpin RNA targeting 14-3-3zeta (named LV-sh14-3-3zeta). Of note, metformin induced apoptosis and retarded tumor growth in the CRCs with overexpressed 14-3-3zeta, whereas this action was attenuated when 14-3-3zeta was knocked down. Moreover, either metformin or downregulation of 14-3-3zeta noticeably activated AMP-dependent protein kinase (AMPK) signaling, whereas the effect of metformin was attenuated when the 14-3-3zeta expression was decreased. Taken together, our results suggest that 14-3-3zeta may be associated with carcinogenesis and poor prognosis of CRCs associated with diabetes, and metformin may reverse the AMPK inhibition caused by 14-3-3zeta in CRCs in the background of diabetes. Our study should lead to a better understanding of the anticancer activity of metformin and points to possible application of metformin to the treatment of cancers overexpressing 14-3-3zeta.

• Authors: Jing Ding, Yue-Ting Zhu, Lie Yang, Jie Tang, Yu-Yi Wang, Ye Chen, Ke Cheng, Jia-Qi Liu, Yun-Ni Zhang, Zhi-Ke Li, Yang Du, Meng Qiu, Ji-Yan Liu
• Journal: Carcinogenesis (Carcinogenesis) Vol. 39 Issue 3 Pg. 493-502 (03 08 2018) ISSN: 1460-2180 [Electronic] England
• PMID: 29390122 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 14-3-3 Proteins
• Antineoplastic Agents
• Hypoglycemic Agents
• Metformin

Topics

• 14-3-3 Proteins (metabolism)
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Colorectal Neoplasms (complications, metabolism, pathology)
• Diabetes Complications (metabolism)
• Diabetes Mellitus (metabolism)
• Female
• Humans
• Hypoglycemic Agents (pharmacology)
• Male
• Metformin (pharmacology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Xenograft Model Antitumor Assays