An isocorydine derivative (d-ICD) inhibits drug resistance by downregulating IGF2BP3 expression in hepatocellular carcinoma.
In our previous studies, we reported that CD133(+) cancer stem cells (CSCs) were chemoresistant in hepatocellular carcinoma (HCC) and that isocorydine treatment decreased the percentage of CD133(+) CSCs. Here, we found that a derivative of isocorydine (d-ICD) inhibited HCC cell growth, particularly among the CD133(+) subpopulation, and rendered HCC cells more sensitive to sorafenib treatment. d-ICD inhibited IGF2BP3 expression in a time-dependent manner, and IGF2BP3 expression negatively correlated with d-ICD-induced growth suppression. IGF2BP3 overexpression enriched the CD133(+) CSC subpopulation in HCC, enhanced tumor sphere formation and suppressed the cytotoxic effects of sorafenib and doxorubicin. The expression of drug resistance-related genes, including ABCB1 and ABCG2, and the CSC marker CD133 expression was increased after IGF2BP3 overexpression. The significance of these observations was underscored by our findings that high IGF2BP3 expression predicted poor survival in a cohort of 236 patients with HCC and positively correlated with ABCG2 and CD133 expression in vivo. These results suggested that the d-ICD may inhibit HCC cells growth by IGF2BP3 decrease and that IGF2BP3 may serve as a therapeutic target for HCC.
School of Basic Medical Science, Shanghai Medical College, Fudan University, Shanghai, China.|State Key Laboratrory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Meng
M
Li
State Key Laboratrory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Lixing
L
Zhang
State Key Laboratrory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Chao
C
Ge
School of Basic Medical Science, Shanghai Medical College, Fudan University, Shanghai, China.|State Key Laboratrory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Lijuan
L
Chen
State Key Laboratrory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Tao
T
Fang
State Key Laboratrory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Hong
H
Li
State Key Laboratrory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Hua
H
Tian
Key Laboratory of Chemistry of Northwestern Plant Resources and Key Laboratory Fornatural Medicine of Gansu Province, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou, China.
Junxi
J
Liu
Qi Dong Liver Cancer Institute, Qi Dong People's Hospital, Qi Dong, Jiangsu Province, China.
Taoyang
T
Chen
Department of General Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Guoping
G
Jiang
Department of General Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Haiyang
H
Xie
Cancer Institute of Guangxi, Guangxi Medical University, Nanning, China.
Ying
Y
Cui
State Key Laboratrory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Ming
M
Yao
State Key Laboratrory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Jinjun
J
Li
D000071916:AC133 Antigen; D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001060:Aporphines / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010455:Peptides / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000077157:Sorafenib; D016019:Survival Analysis; D013997:Time Factors; D014162:Transfection
C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D000071916:AC133 Antigen; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000903:Antibiotics, Antineoplastic; D015703:Antigens, CD; D000970:Antineoplastic Agents; D001060:Aporphines; D014408:Biomarkers, Tumor; D006023:Glycoproteins; C498780:IGF2BP3 protein, human; D009363:Neoplasm Proteins; C000606023:PROM1 protein, human; D010455:Peptides; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D016601:RNA-Binding Proteins; D009536:Niacinamide; C030168:isocorydine; D004317:Doxorubicin; D000077157:Sorafenib
CD133; IGF2BP3; cancer stem cell; hepatocellular carcinoma; isocorydine