Apoptosis induced by chemotherapeutic agents involves c-Jun N-terminal kinase activation in sarcoma cell lines.
Molecular mechanisms underlying chemotherapeutic agent-induced apoptosis in sarcoma cells are not well known. Induction of apoptosis is regulated by several components including mitogen-activated protein kinases (MAPKs) comprising ERK, p38MAPKs, and c-Jun N-terminal kinase (JNK). In the present study, we examined whether activation of JNK is induced by the chemotherapeutic agents cis-diaminedichloroplatinum (cisplatin, CDDP) or doxorubicin (DXR), and whether the ectopic expression of constitutively active (MKK7-JNK1) or dominant-negative form of JNK (dnJNK) influenced apoptosis in response to the CDDP or DXR in sarcoma cell lines MG-63 and SaOS-2. The CDDP or DXR induced JNK activation in the both cell lines, as assessed by Western blotting using phosphospecific antibodies. A transient expression of the activated form of JNK sensitized the MG-63 and SaOS-2 cells to the drug-induced apoptosis, while dnJNK1 reduced the proportion of apoptotic cell death. Apoptosis was determined by flow cytometry using annexin-V Cy5. Collectively, our results indicate that JNK activation is involved in apoptotic cell death in sarcoma cell lines following stimulation with CDDP or DXR.
Koyama
Takaaki
T
Department of Immunology, Tokyo Medical University, Tokyo, 160-8402 Japan.
Mikami
Takashi
T
Koyama
Takashi
T
Imakiire
Atsuhiro
A
Yamamoto
Kengo
K
Toyota
Hiroko
H
Mizuguchi
Junichiro
J
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D006801:Humans; D007527:Isoenzymes; D048055:Mitogen-Activated Protein Kinase 8 / Q000096:biosynthesis*; D012509:Sarcoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology
D000970:Antineoplastic Agents; D007527:Isoenzymes; D004317:Doxorubicin; D048055:Mitogen-Activated Protein Kinase 8; D002945:Cisplatin