Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, China.
Department of Oncology, Cancer Hospital Affiliate to School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
Carcinogenesis. 2018 Mar 8;39(3):493-502. doi: 10.1093/carcin/bgy008.
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.
二甲双胍是一种有前途的癌症预防和治疗药物，尤其在糖尿病患者中。我们旨在测试 14-3-3zeta 是否影响二甲双胍对结直肠癌（CRC）的抗癌作用。在这项研究中，我们证实 CRC 组织中的 14-3-3zeta 表达高于癌旁组织，糖尿病患者的 CRC 组织中高于非糖尿病患者。敲低 14-3-3zeta 抑制 CRC 的体外和体内增殖并促进凋亡。然后，我们通过携带靶向 14-3-3zeta 的短发夹 RNA 的慢病毒载体感染 SW480 和 HCT15 细胞，从这些细胞中创建了 14-3-3zeta 表达下调的稳定细胞系（命名为 LV-sh14-3-3zeta）。值得注意的是，二甲双胍在 14-3-3zeta 过表达的 CRC 中诱导凋亡并抑制肿瘤生长，而当 14-3-3zeta 被敲低时，这种作用减弱。此外，无论是二甲双胍还是 14-3-3zeta 的下调，都明显激活了 AMP 依赖的蛋白激酶（AMPK）信号通路，而当 14-3-3zeta 表达降低时，二甲双胍的作用减弱。总之，我们的结果表明，14-3-3zeta 可能与糖尿病相关的 CRC 的发生和不良预后有关，而二甲双胍可能逆转 14-3-3zeta 在糖尿病背景下 CRC 中引起的 AMPK 抑制。我们的研究应该有助于更好地理解二甲双胍的抗癌活性，并指出可能将二甲双胍应用于治疗过表达 14-3-3zeta 的癌症。
