Cancer Letters 481 (2020) 32–44 Contents lists available at ScienceDirect Cancer Letters

 Cancer Letters 481 (2020) 32–44 Contents lists available at ScienceDirect Cancer Letters journal homepage: www.elsevier.com/locate/canlet Original Articles Microbiota-derived SSL6 enhances the sensitivity of hepatocellular T carcinoma to sorafenib by down-regulating glycolysis 1 1 Xiao Zhang , Lei Wu , Yanquan Xu, Hua Yu, Yu Chen, Huakan Zhao, Juan Lei, Yu Zhou, ∗ Jiangang Zhang, Jingchun Wang, Jin Peng, Lu Jiang, Halei Sheng, Yongsheng Li ClinicalMedicineResearchCenter,XinqiaoHospital,ArmyMedicalUniversity,Chongqing,400037,China ARTICLE INFO ABSTRACT Keywords: Enhancing the sensitivity of hepatocellular carcinoma (HCC) to sorafenib (SFN) is an essential clinical CD47 bottlenecktobesolved.HerewereportthattheexpressionofCD47negativelycorrelatedwithHCCsensitivityto Sorafenib sensitivity SFN CH 223191. The microbiota-derived Staphylococcal superantigen-like protein 6 (SSL6) inhibited CD47 and promoted Staphylococcal superantigen-like protein SFN-induced apoptosis of HCC cells Huh-7 and MHCC97H. Mechanistically, the sensitivity of HCC cells to SFN Glycolysis 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 HCCcells exhibited enhancedglycolysis and CD47expression. 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. 1. Introduction [10–12]. However, antibody treatment has many drawbacks, such as short half-life, high cost, and antibody-dependent cytotoxicity (ADCC) Hepatocellular carcinoma (HCC) ranks the second in malignant tu- and complement-dependent cytotoxicity (CDC) mediated by antigen- morswithamortalityrateof82%[1 NSC232003,2].Sorafenib(SFN)isthestandard antibody reaction, which severely limited their application in anti- first-line targeted drug for advanced HCC treatment [3,4]. 

 

However, tumor therapy [14,15]. Therefore, developing drugs or compounds various HCC cells have distinct sensitivities to SFN, and acquire re- blocking CD47 that are inexpensive, side effect-less to enhance the sistance to ###http://www.glpbio.com/simage/GA11233-L-NAME-hydrochloride-1.png####SFN [5,6]. Therefore, enhancing the sensitivity of HCC cells sensitivity of HCC cells to SFN is of interest and importance. to SFN is of great significance for improving the prognosis of HCC pa- Inrecentyears,microbiotahasgraduallybecomearesearchhotspot tients. in developing new strategy for cancer treatment [16–18] Dexmedetomidine. Some bac- Immunecheckpointsplayaveryimportantroleinpromotingtumor teria and their metabolites have significant anti-tumor effects. For in- immune escape [7]. Clinical studies have found that targeted therapy stance,Bifidobacteria exerts the anti-tumor efficacy by interfering with combined with immunotherapy blocking immunological checkpoints signaling pathways such as CTLA-4 and PD-1 [19,20]. Some Gram-po- can exert synergistic anti-tumor effects [8].

 

 In addition to CTLA-4 and sitive bacteria induces specific immune responses in tumor-bearing PD-1/PD-L1, other new immune checkpoint molecules have been re- mice and enhances the tumor sensitivity to chemotherapy [21]. Clos- ported, such as the cell surface transmembrane glycoprotein CD47 [9]. tridium, Salmonella and Listeria, whose toxicities have been attenuated CD47isalwayshighlyexpressedintumorcells,anditsexpressionlevel by genetic editing, have shown significantanti-tumor effects in clinical is inversely related to the prognosis of the patients [10–12]. Interest- trials of melanoma, renal and cervical cancer, respectively [22–24]. ingly, earlier studies found that CD47 molecules may also mediate the Bacteria-derived toxins such as Pseudomonas aeruginosa exotoxin A, tolerance response of HCC cells to SFN [13]. In view of the fact that enterotoxin andS.aureus α-toxin promote the apoptosis of tumor cells blocking CD47 molecular signals can promote anti-tumor therapy via [25–27]. Bacteria-derived protein azurin induces the apoptosis of multiple mechanisms, a variety of CD47 monoclonal antibodies were melanoma cells [28]. Therefore, the development of bacterial-related applied in clinical trials and some showed promising anticancer effects toxins or proteins for anti-tumor therapy has important research ∗ Corresponding author. E-mailaddress: yli@tmmu.edu.cn (Y. Li). 1 Xiao Zhang and Lei Wu contributed equally to this work. https://doi.org/10.1016/j.canlet.2020.03.027 Received 18 November 2019; Received in revised form 18 March 2020; Accepted 26 March 2020 0304-3835/ © 2020 Elsevier B.V. All rights reserved.