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Long‐term activation of SAPK/JNK, p38 kinase and fas‐L expression by cisplatin is attenuated in human carcinoma cells that acquired drug resistance
Author(s) -
Brozovic Anamaria,
Fritz Gerhard,
Christmann Markus,
Zisowsky Jochen,
Jaehde Ulrich,
Osmak Maja,
Kaina Bernd
Publication year - 2004
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.20522
Subject(s) - cisplatin , apoptosis , p38 mitogen activated protein kinases , kinase , downregulation and upregulation , fas ligand , protein kinase a , cancer research , hela , cell culture , microbiology and biotechnology , chemistry , biology , medicine , programmed cell death , chemotherapy , biochemistry , gene , genetics
Tumor cells chronically exposed to cisplatin (cDDP) acquire cDDP resistance that impacts tumor therapy. To elucidate the mechanism of acquired cDDP resistance (ACR), we compared HeLa cells that gained ACR upon chronic cDDP treatment with the parental strain. We show that ACR is due to a lower level of induced apoptosis. Further, upon cDDP treatment, the levels of Fas, Bax and Bid remained unchanged, whereas Bcl‐2 and p‐Bad were reduced at late times (120 hr) after treatment. At early times, Fas ligand ( fas ‐L) expression was significantly enhanced in sensitive compared to resistant cells and remained upregulated up to the onset of apoptosis. Thus, activation of the Fas system is critical, which is in line with the finding that in sensitive cells, caspase‐8 along with caspase‐9 and ‐3 were activated by cDDP. cDDP provoked the activation of stress‐activated protein kinase/c‐Jun N‐terminal kinase (SAPK/JNK) and p38 kinase dose‐dependently, with significantly lower levels in ACR cells than in the sensitive parental line. cDDP induces c‐Jun and AP‐1 activity, as measured by a reporter gene assay, which was again attenuated in ACR cells. Time course analysis revealed that SAPK/JNK and p38 kinase activity was sustained upregulated (> 72 hr postexposure), which occurred at much higher level in sensitive than in ACR cells. Inhibition of either JNK or p38 kinase (by JNK inhibitor II and SB 203580, respectively) attenuated cDDP‐induced apoptosis, supporting the role of JNK and p38 kinase in the cDDP response. Since several independently derived cDDP‐resistant cell lines displayed attenuated MAPK signaling, sustained SAPK/JNK and p38 kinase activation may be a general mechanism of cDDP‐induced cell death. ACR cells displayed a reduced level of DNA damage, indicating long‐term stimulation of SAPK/JNK and p38 kinase is triggered by nonrepaired cDDP‐induced DNA lesions. © 2004 Wiley‐Liss, Inc.