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.
Highlights
Autophagy is a conserved intracellular degradation process in which cellular organelles are degraded by lysosomes and recycled to replenish cells with energy in stress environments
We found that AMPK is involved in metformin-induced CCAAT/enhancer-binding protein delta (CEBPD) expression
The results showed that the growth arrest and apoptosis of Huh7 cells were coordinately increased following the metformin treatment (Figure 1A and Supplementary Figure 1A)
Summary
Autophagy is a conserved intracellular degradation process in which cellular organelles are degraded by lysosomes and recycled to replenish cells with energy in stress environments. As an essential regulator of cellular homeostasis and adaptation of stresses, autophagy plays an important role in carcinogenesis including hepatocellular carcinoma (HCC). Understanding the details of the involvement of autophagy in HCC is crucial to help facilitate the development of future therapeutic approaches to HCC. Autophagy related genes (ATGs) are vital for phagophore formation, and microtubule-associated protein light chain 3 (LC3B, known as ATG8) is one of the most important phagophore components. In HCC, p62 expression increases, and the autophagy response is impaired [3]. The regulation of ATGs and their involvement in HCC cancer cells remain largely uncharacterized
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