Sorafenib with ASC-J9®synergistically suppresses the HCC progression via altering the pSTAT3-CCL2/Bcl2 signals.
Sorafenib is currently used as a standard treatment to suppress the progression of hepatocellular carcinoma (HCC), especially in advanced stages. However, patients who receive Sorafenib treatment eventually develop resistance without clear mechanisms. There is a great need for better efficacy of Sorafenib treatment in combination with other therapies. Here, we demonstrated that the treatment combining Sorafenib with ASC-J9®could synergistically suppress HCC progression via altering cell-cycle regulation, apoptosis and invasion. Mechanism dissection suggests that while Sorafenib impacts little or even slightly increases the activated/phosphorylated STAT3 (p-STAT3), a key stimulator to promote the HCC progression, adding ASC-J9®significantly suppresses the p-STAT3 expression and its downstream genes including CCL2 and Bcl2. Interrupting these signals via constitutively active STAT3 partially reverses the synergistic suppression of Sorafenib-ASC-J9®combination on HCC progression. In vivo studies further confirmed the synergistic effect of Sorafenib-ASC-J9®combination. Together, these results suggest the newly developed Sorafenib-ASC-J9®combination is a novel therapy to better suppress HCC progression.
Chawnshang Chang Liver Cancer Center, Departments of General Surgery and Urology, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China.|George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA.
Junjie
J
Xu
Chawnshang Chang Liver Cancer Center, Departments of General Surgery and Urology, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China.
Hui
H
Lin
Chawnshang Chang Liver Cancer Center, Departments of General Surgery and Urology, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China.
Gonghui
G
Li
George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA.
Yin
Y
Sun
Chawnshang Chang Liver Cancer Center, Departments of General Surgery and Urology, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China.|George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA.
Liang
L
Shi
Sex Hormone Research Center, China Medical University/Hospital, Taichung, Taiwan.
Wen-Lung
WL
Ma
Chawnshang Chang Liver Cancer Center, Departments of General Surgery and Urology, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China.
Jiang
J
Chen
Chawnshang Chang Liver Cancer Center, Departments of General Surgery and Urology, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China.
Xiujun
X
Cai
George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA.|Sex Hormone Research Center, China Medical University/Hospital, Taichung, Taiwan.
Chawnshang
C
Chang
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000378:metabolism*; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology; D018450:Disease Progression; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000379:methods; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib
D018932:Chemokine CCL2; D003474:Curcumin; D009536:Niacinamide; D010671:Phenylurea Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; D000077157:Sorafenib; C471106:ASC-J9 compound; C000595707:BCL2 protein, human; C111835:CCL2 protein, human; C494086:STAT3 protein, human
ASC-J9®; Sorafenib; hepatocellular carcinoma; synergism
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