P14ARF sensitizes human osteosarcoma cells to cisplatin-induced apoptosis in a p53-independent manner.
The tumor suppressor p14ARF, encoded by the INK4a/ARF locus, is often disrupted in human cancers, p14ARF triggers cell cycle arrest and sensitizes cells to apoptosis in the presence of collateral signals. To investigate the role of p14ARF in chemotherapeutic drugs-induced apoptosis, p14ARF was overexpressed by stable transfection in human osteosarcoma cell lines, U2OS (p53-wt/p14ARF-null) and MG63 (p53-mt/p14ARF-null). The results showed that ectopic p14ARF sensitized both cell lines to cisplatin-induced cytotoxicity and apoptosis. This sensitization of cisplatin-induced apoptosis was associated with upregulation of p53, Bax and p21 in U2OS cells. Conversely, such a result was not observed in MG63 cells. Moreover, the sensitization of cisplatin-induced cytotoxicity in U2OS cells was unaltered by p53 siRNA. Together, we show here p14ARF sensitizes human osteosarcoma cells to cisplatin-induced apoptosis in a p53-independent manner. Proper combinations of p14ARF gene transfer and conventional chemotherapy may be a valuable strategy in human osteosarcoma treatment.
Yuan
Xiang-Wei
XW
Department of Orthopedic Surgery, The First Affiliated Hospital, Cancer Center, Sun Yat-sen University, Guangzhou, PR China.
Zhu
Xiao-Feng
XF
Huang
Xiu-Fang
XF
Sheng
Pu-Yi
PY
He
Ai-Shan
AS
Yang
Zi-Bo
ZB
Deng
Rong
R
Feng
Gong-Kan
GK
Liao
Wei-Ming
WM
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D006801:Humans; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000032:analysis; D014162:Transfection; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000502:physiology*; D019014:fas Receptor / Q000032:analysis
D000970:Antineoplastic Agents; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D002945:Cisplatin