Transfection of Smac sensitizes tumor cells to etoposide-induced apoptosis and eradicates established human hepatoma in vivo.
A major concern in clinical treatment of cancers is resistance of tumors such as hepatocellular carcinoma (HCC) and osteosarcoma to current chemotherapy protocols. Here, we reported that overexpression of second mitochondria-derived activator of caspase (Smac) sensitized osteosarcoma cells and HCC cells in vitro to chemotherapeutic drugs-induced apoptosis. Constitutive expression of Smac resulted in enhanced Bax accumulation on mitochondria upon etoposide stimulation and inhibited Bcl-2-induced antiapoptosis activity. Thus, Smac would sensitize tumor cells to chemotherapeutic drugs in part through promoting Bax translocation to mitochondria and bypassing Bcl-2 block. Moreover, we demonstrated that blockade of Smac expression by antisense smac did not impair etoposide-induced apoptosis; however, p53-induced apoptosis was impaired in smac deficient Saos-2 cell. This suggested Smac might be required in p53-induced apoptosis. Most importantly, complete eradication of HepG2 xenografts in vivo was achieved upon combined therapy with Ad-Smac and 5-Fu. Thus, overexpression of Smac in tumor cells might be a potent strategy for cancer treatment by sensitization of tumor cells to chemotherapeutic drugs.
Zhao
J
J
International Joint Cancer Institute, E-Institute of Shanghai Universities and Eastern Hospital of Hepatobiliary Surgery, The Second Military Medical University, Shanghai, PR China.
Jin
J
J
Zhang
X
X
Shi
M
M
Dai
J
J
Wu
M
M
Wang
R
R
Guo
Y
Y
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001859:Bone Neoplasms; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005047:Etoposide; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use; D015316:Genetic Therapy; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D012516:Osteosarcoma; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D005047:Etoposide; D005472:Fluorouracil