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.

[Retracted] Overexpression of 14‐3‐3δ Predicts Poor Prognosis in Extrahepatic Cholangiocarcinoma Patients

“…Elevated expression of 14-3-3 δ protein have been reported recently in head and neck squamous cell carcinomas [ 10 ], liver cancer [ 11 ], nonsmall cell lung cancer, colorectal carcinoma [ 12 ], and breast cancer [ 13 ]. In our previous study, we also found the level of 14-3-3 δ protein is elevated in cholangiocarcinoma, but the samples contained a large portion of intrahepatic CCA [ 14 ], the role and expression of 14-3-3 δ in the development of extrahepatic CCA has not been well studied so far.…”

A high-throughput screening approach to discover potential colorectal cancer chemotherapeutics: Repurposing drugs to disrupt 14-3-3 protein-BAD interactions

“…The overexpression of 14-3-3ζ and its related isoforms in the context of cancer has long been associated with poor clinical outcomes due to increased cell survival [15, 42] . Although it has been demonstrated that inhibiting 14-3-3ζ triggers apoptosis in cancer cells, there are currently no approved chemotherapies that target 14-3-3ζ:BAD interactions [17] . The primary aim of this study was to explore the possibility of identifying anti-CRC compounds by their capacity to interrupt 14-3-3ζ:BAD interactions, and this was executed by the generation of a biosensor capable of detecting 14-3-3ζ:BAD PPIs.…”

“…Alterations in 14-3-3 protein expression, especially the 14-3-3ζ isoform, have been observed in a variety of cancers, such as those of colon, breast, lung, and pancreas [15] , and overexpression of 14-3-3ζ may mediate tumor resistance to chemotherapy due to its anti-apoptotic functions [16] . Depletion of 14-3-3ζ has been found to induce the apoptosis of CRC cells in vitro and in vivo [17] , and suggesting that identifying or developing novel disruptors of 14-3-3 protein:BAD protein-protein interactions (PPIs) might represent a promising approach towards the treatment of various cancers, including CRC. Drug development involving de novo synthesis and validation of novel chemical entitites is an incredibly expensive and time-consuming endeavor that typically yields a low success rate [18][19][20] .…”

Metformin in therapeutic applications in human diseases: its mechanism of action and clinical study

“…Accordingly, the AMPK-dependent effect of metformin has been implied to be beneficial for many other pathogeneses, such as cancer [70]. For the critical role of cancer stem/initiating cells in tumorigenesis and cancer development, researchers explored whether metformin affects cancer initiating cells, and found that metformin (1 mM) activates hexaribonucleotide-binding protein 3(FOX3) via AMPK activation, which is sufficient to promote the differentiation of glioma-initiating cells into nontumorigenic cells [71].…”