Metformin promotes apoptosis in hepatocellular carcinoma through the CEBPD-induced autophagy pathway

Abstract

Metformin, as an AMP-activated protein kinase (AMPK) activator, can activate autophagy. A study showed that metformin decreased the risk of hepatocellular carcinoma (HCC) in diabetic patients. However, the detailed mechanism in the metformin-mediated anticancer effect remains an open question. Transcription factor CCAAT/enhancer-binding protein delta (CEBPD) has been suggested to serve as a tumor suppressor and is responsive to multiple anticancer drugs in HCC. In this study, we found that CEBPD and autophagy are involved in metformin-induced cell apoptosis in Huh7 cells. The underlying mechanisms in this process included a reduction in Src-mediated CEBPD protein degradation and an increase in CEBPD-regulated LC3B and ATG3 gene transcription under metformin treatment. We also found that AMPK is involved in metformin-induced CEBPD expression. Combined treatment with metformin and rapamycin can enhance autophagic cell death through the AMPK-dependent and AMPK-independent pathway, respectively. Taken together, we provide a new insight and therapeutic approach by targeting autophagy in the treatment of HCC.

Metabolic disorders across hepatocellular carcinoma in Italy

“…8,41 This surprising and difficult to understand discrepancy probably relies on the effect of selection biases and confounding factors on results. Therefore, future studies on this topic should take into account, for instance, insulin and hypoglycaemic drugs (in particular metformin that seems to have strong antineoplastic effects 42,43 ) as factors potentially capable to influence results. This study presents some limitations.…”

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

“…Glucose metabolism and inflammation may not be the only pathomechanisms affected by metformin/NRF2. In fact, other salutary effects have been described for redox (Kocer et al, 2014;Kelleni et al, 2015) and protein homeostasis (Tsai et al, 2017).…”

Sodium glucose cotransporter 2 inhibitor canagliflozin attenuates liver cancer cell growth and angiogenic activity by inhibiting glucose uptake

“…For instance, an epidemiologic analysis revealed an association between metformin, a first‐line medication for the treatment of type 2 diabetes (T2DM), and a reduced risk of HCC development . Basic studies revealed that metformin inhibited HCC cell proliferation, invasion and angiogenesis and induced both apoptosis and autophagy through AMP‐activated protein kinase (AMPK) ‐dependent and ‐independent pathways . In addition, dipeptidyl peptidase 4 inhibitors (DPP4‐Is), which have been developed as a viable option for T2DM therapy, can enhance tumor immunity by stabilizing biologically active forms of C‐X‐C motif chemokine 10 and may thus yield potential therapeutic benefits for cancer patients .…”

“…6 Basic studies revealed that metformin inhibited HCC cell proliferation, invasion and angiogenesis and induced both apoptosis and autophagy through AMP-activated protein kinase (AMPK) -dependent and -independent pathways. 7,8 In addition, dipeptidyl peptidase 4 inhibitors (DPP4-Is), which have been developed as a viable option for T2DM therapy, can enhance tumor immunity by stabilizing biologically active forms of C-X-C motif chemokine 10 and may thus yield potential therapeutic benefits for cancer patients. 9 Our recent study also revealed that DPP4-I exerted preventive effects against murine hepatocarcinogenesis via antiangiogenic and antioxidative activities.…”