Interaction between autophagy and senescence is required for dihydroartemisinin to alleviate liver fibrosis

Abstract

Autophagy and cellular senescence are stress responses essential for homeostasis. Therefore, they may represent new pharmacologic targets for drug development to treat diseases. In this study, we sought to evaluate the effect of dihydroartemisinin (DHA) on senescence of activated hepatic stellate cells (HSCs), and to further elucidate the underlying mechanisms. We found that DHA treatment induced the accumulation of senescent activated HSCs in rat fibrotic liver, and promoted the expression of senescence markers p53, p16, p21 and Hmga1 in cell model. Importantly, our study identified the transcription factor GATA6 as an upstream molecule in the facilitation of DHA-induced HSC senescence. GATA6 accumulation promoted DHA-induced p53 and p16 upregulation, and contributed to HSC senescence. By contrast, siRNA-mediated knockdown of GATA6 dramatically abolished DHA-induced upregulation of p53 and p16, and in turn inhibited HSC senescence. Interestingly, DHA also appeared to increase autophagosome generation and autophagic flux in activated HSCs, which was underlying mechanism for DHA-induced GATA6 accumulation. Autophagy depletion impaired GATA6 accumulation, while autophagy induction showed a synergistic effect with DHA. Attractively, p62 was found to act as a negative regulator of GATA6 accumulation. Treatment of cultured HSCs with various autophagy inhibitors, led to an inhibition of DHA-induced p62 degradation, and in turn, prevented DHA-induced GATA6 accumulation and HSC senescence. Overall, these results provide novel implications to reveal the molecular mechanism of DHA-induced senescence, by which points to the possibility of using DHA based proautophagic drugs for the treatment of liver fibrosis.

Dihydroartemisinin induces apoptosis and autophagy‐dependent cell death in cholangiocarcinoma through a DAPK1‐BECLIN1 pathway

“…Similarly, DHA could be used in combinatorial therapies to treat BCL‐2‐dependent chemoresistant CCAs. The recent finding that DHA alleviates liver fibrosis through induction of autophagy in hepatic stellate stem cells further supports its chemotherapeutic potential in the treatment of CCA . Taken together, the data available in the literature along with the data here reported support pre‐clinical studies to confirm the therapeutic potential of DHA in CCA models, and in clinical trials in CCA patients.…”

“…Interestingly, DHA could alleviate liver fibrosis through autophagy-mediated induction of senescence in hepatic stellate stem cells. 21 Here, we show that DHA is toxic to CCA cells, while being mildly toxic toward normal cholangiocytes. DHA killed CCA cells through both apoptosis and autophagy-dependent cell death, two modalities of cell death that do not elicit an inflammatory reaction.…”

“…Moreover, DHA was shown to interfere with the PDGF‐βR/ERK signaling pathway in hepatic stellate cells and so alleviating bile duct ligation‐induced liver fibrosis . In a recent study, DHA could alleviate liver fibrosis through autophagy‐mediated induction of senescence in hepatic stellate stem cells . On testing DHA on six CCA cell lines and on immortalized cholangiocytes, we found that DHA elicited toxicity preferentially toward CCA cells.…”

“…20 In a recent study, DHA could alleviate liver fibrosis through autophagy-mediated induction of senescence in hepatic stellate stem cells. 21 On testing DHA on six CCA cell lines and on immortalized cholangiocytes, we found that DHA elicited toxicity preferentially toward CCA cells. The IC50 for DHA in the CCA cell lines tested was in the range of 53-61 μM, and the final concentration used to induce cell death was 50 μM, that is in the range of the concentration used in similar in vitro and in vivo studies performed in a variety of cancer types 43,44 including cholangiocarcinoma, 45 hepatocarcinoma, 45 pancreatic cancer, 46,47 lung cancer, 48 18,19,51 and autophagy 12,15,52 in cancer cells.…”

“…Since DHA has been proven to kill hepatomas and to reduce fibrosis in the liver following bile duct ligation, we reasoned that it could be a good candidate chemotherapeutics for CCA. Interestingly, DHA could alleviate liver fibrosis through autophagy‐mediated induction of senescence in hepatic stellate stem cells …”