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Published on: September 12, 2019
Microbiota-derived SSL6 enhances the sensitivity of hepatocellular carcinoma to sorafenib by down-regulating
Xiao Zhang1, Lei Wu1, Yanquan Xu1
1Clinical Medicine Research Center, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.
Abstract:
Enhancing the sensitivity of hepatocellular carcinoma (HCC) cells to sorafenib (SFN) is an essential clinical bottleneck to be solved. Here we report that the expression of CD47 negatively correlated with HCC sensitivity to SFN. The microbiota-derived Staphylococcal superantigen-like protein 6 (SSL6) inhibited CD47 and promoted SFN-induced apoptosis of HCC cells Huh-7 and MHCC97H. Mechanistically, the sensitivity of HCC cells to SFN was inhibited by elevated Warburg effect (glycolysis), and SSL6 down-regulated PI3K/Akt-mediated glycolysis by blocking CD47. Knockdown of CD47 also dampened glycolysis and sensitized HCC cells to SFN. Moreover, SFN-resistant HCC cells exhibited enhanced glycolysis and CD47 expression. SSL6 significantly re-sensitized the resistant HCC cells to SFN. More importantly, we identified the anti-tumor effect of SSL6 in combination with SFN in HCC-bearing mice. Our results clarify the mechanism by which SSL6 enhances SFN sensitivity in HCC cells, providing a molecular basis for combination targeted therapy with microbiota-derived SSL6 to treat HCC.
Insights
Microbiota-derived Staphylococcal superantigen-like protein 6 (SSL6) enhances hepatocellular carcinoma (HCC) sensitivity to sorafenib (SFN) by inhibiting CD47 and reducing glycolysis. This combination therapy shows anti-tumor effects in mice.
Area of Science:
- Oncology
- Microbiology
- Pharmacology
Background:
- Hepatocellular carcinoma (HCC) exhibits resistance to sorafenib (SFN), a major clinical challenge.
- CD47 expression is inversely correlated with HCC sensitivity to SFN.
- The Warburg effect (glycolysis) contributes to SFN resistance in HCC cells.
Purpose of the Study:
- To investigate the role of microbiota-derived Staphylococcal superantigen-like protein 6 (SSL6) in overcoming SFN resistance in HCC.
- To elucidate the molecular mechanisms underlying SSL6's effect on HCC sensitivity to SFN.
Main Methods:
- Assessing the correlation between CD47 expression and SFN sensitivity in HCC cell lines (Huh-7, MHCC97H).
- Evaluating the effect of SSL6 on CD47 expression, glycolysis, and SFN-induced apoptosis.
- Investigating the PI3K/Akt signaling pathway.
- Testing the efficacy of SSL6 and SFN combination therapy in HCC-bearing mice.
Main Results:
- SSL6 inhibited CD47 expression and promoted SFN-induced apoptosis in HCC cells.
- SSL6 down-regulated PI3K/Akt-mediated glycolysis by blocking CD47, thereby enhancing SFN sensitivity.
- CD47 knockdown mimicked SSL6's effect by reducing glycolysis and sensitizing HCC cells to SFN.
- SSL6 re-sensitized SFN-resistant HCC cells, which showed high glycolysis and CD47 expression.
- Combination therapy of SSL6 and SFN demonstrated anti-tumor effects in vivo.
Conclusions:
- SSL6 enhances HCC sensitivity to SFN by targeting the CD47-mediated glycolysis pathway.
- This study provides a molecular basis for combining microbiota-derived SSL6 with SFN for HCC treatment.
