Protective autophagy induced by physcion suppresses hepatocellular carcinoma cell metastasis by inactivating the JAK2/STAT3 Axis.

AIM: Although the anti-neoplastic effects of physcion are well documented, its specific action in hepatocellular carcinoma (HCC) is not understood. Taken together, physcion is a promising drug candidate for the treatment and prevention of HCC.

MATERIAL AND METHODS: Cell Counting Kit-8 (CCK-8) assay utilized to examine the viability of Hep3B and SMMC7721 cells. Apoptotic cell population was measured by flow cytometry analysis assay. Cell migration and cell invasion were determined by wound healing and Transwell assay. Autophagy was determined by mRFP-GFP-LC3 adenovirus infection and monodansylcadaverine (MDC) staining. Western blot analysis was performed to examine the level of marker proteins in ovarian cancer cells. Moreover, xenograft model was established to evaluate the therapeutic effect of physcion in vivo.

KEY FINDINGS: We found that physcion inhibited proliferation, migration and invasion of HCC cells, and promoted apoptosis and autophagy in the HCC cells. Physcion-induced autophagy reduced the percentage of apoptotic cells, as well as the levels of pro-apoptotic proteins in the HCC cells. Pharmacological inhibition of autophagy with 3-MA, or Atg 5 knockdown, reversed this autophagy-mediated apoptosis inhibition, indicating a pro-survival role of the former in HCC. Furthermore, suppressing autophagy also abrogated the inhibitory effect of physcion on HCC cell migration and invasion, indicating that autophagy is essential for its anti-metastatic effects. Physcion induced protective autophagy by inactivating the JAK2-STAT3 pathway, and activating the latter by IL-6 reversed the pro-survival effects of autophagy.

SIGNIFICANCE: Physcion is a promising drug candidate for the treatment and prevention of HCC.