Metformin-induced caveolin-1 expression promotes T-DM1 drug efficacy in breast cancer cells

Abstract

Trastuzumab emtansine (T-DM1) is an antibody drug conjugate (ADC) that was recently approved for the treatment of HER-2-positive metastatic breast cancer. The drug sensitivity of ADCs depends mainly on the internalization efficiency of the drug. Caveolin-1 was shown to promote T-DM1 internalization and enhance drug sensitivity. Whether caveolin-1 can be overexpressed to improve T-DM1 efficacy is interesting and has the potential for clinical application. In this study, diabetes drug metformin was investigated in terms of induction of caveolin-1 expression for increased efficacy of subsequent T-DM1 application. BT-474 cells were pretreated with metformin, followed by combined therapy with metformin and T-DM1. The T-DM1 internalization and drug efficacy were determined, and the protein expressions for signal transduction were also monitored. Caveolin-1 shRNA was applied to suppress endogenous caveolin-1 expression, and the ability of metformin to promote T-DM1 efficacy was investigated. Result showed that in BT-474 cells pretreated with metformin, cellular caveolin-1 overexpression was induced, which then promoted drug efficacy by enhancing T-DM1 internalization. As cellular caveolin-1 was suppressed by shRNA, the effect of metformin-enhanced T-DM1 cytotoxicity was decreased. This study demonstrated that metformin can be applied prior to T-DM1 treatment to improve the clinical efficacy of T-DM1 by enhancing caveolin-1-mediated endocytosis.

Role of Caveolin-1 in Diabetes and Its Complications

“…Oxidative Medicine and Cellular Longevity where their sensitivity to metformin was dependent on CAV1 expression and CAV1 was required to induce AMPK phosphorylation and the increase in the AMP/ATP ratio [196]. Metformin induces CAV1 expression [197], which in return increases clinical efficacy of drug delivery (trastuzumab emtansine) in breast cancer cells [198]. Sulphonylureas on the other hand increase insulin release by blocking K ATP channels [199].…”

Hypoxia Attenuates Trastuzumab Uptake and Trastuzumab-Emtansine (T-DM1) Cytotoxicity through Redistribution of Phosphorylated Caveolin-1

“…Chung and colleagues (26) suggested that CAV1 promotes chemosensitivity to T-DM1, whereas others, on the contrary, reported that the acquisition of TDM1 resistance is due to deficient cleavage of T-DM1 in CAV1-associated endosomes (28). In favor of a role of CAV1 in promoting T-DM1 sensitivity, increased CAV1 expression by metformin was shown to induce T-DM1 internalization and subsequent cytotoxicity (27). Our data strongly support the concept of a dependence on vesicular, raft-associated CAV1 for efficient T-DM1 cytotoxic activity.…”

“…Moreover, hypoxia may augment ligand-independent EGFR signaling by increased dimerization and prolonged activation in caveolin-1 (CAV1)-associated membrane domains, further leading to enhanced tumor cell proliferation and invasiveness (21). Hypoxia was shown to downregulate membrane protein internalization through a mechanism that involved CAV1 (22), and other studies suggest that HER2 homodimers codistribute with cholesterol-rich membrane raft domains and an involvement of caveolae-dependent mechanisms in the regulation of HER2 trafficking (23)(24)(25)(26)(27)(28). Importantly, the possible link between hypoxia, HER2 internalization, and T-DM1 resistance remains unexplored.…”

Novel application of metformin combined with targeted drugs on anticancer treatment

“…The phase III EMILIA trial showed trastuzumab emtansine, an Ab conjugate, significantly prolonged the PFS and OS in metastatic breast cancer patients. Metformin promotes trastuzumab emtansine drug efficacy through inducing caveolin‐1 expression in breast cancer . As for some HER2‐positive breast carcinomas patients after trastuzumab treatment, lapatinib was usually used to inhibit cancer progression.…”

“…Metformin promotes trastuzumab emtansine drug efficacy through inducing caveolin-1 expression in breast cancer. 57 As for some HER2-positive breast carcinomas patients after trastuzumab treatment, lapatinib was usually used to inhibit cancer progression. Metformin could be a clinically useful candidate of delaying or treating lapatinib resistance by inactivating mTOR and decreasing p70S6K1 activity.…”