Role of Jun and Jun kinase in resistance of cancer cells to therapy.
A series of kinases, the mitogen-activated protein (MAP) kinases, serves to regulate cellular responses to various environmental influences in metazoans. Three major pathways have been described, each with some overlap in substrate specificity that causes activation of parallel pathways. The activation of one of these, the Jun kinase pathway, has been implicated in apoptotic responses to DNA damage, cell stress and cytotoxic drugs. Under most circumstances in non-malignant cells it appears that c-Jun N-terminal kinase (JNK) activation is a pro-apoptotic event that results in turn in activation of pro-apoptotic members of Bcl-2 family and cytochrome c release from mitochondria. In cells with dysregulated/mutated proliferation or cell cycle controls, the role of JNK and of c-Jun is more controversial. We distinguish between the transcriptional effects of JNK and other protein interactions in which it participates. The initiation of mitochondrial apoptosis pathways by JNK is independent of its transcriptional effects for the most part. In certain cell types, c-Jun overexpression is clearly a basis for resistance to DNA-damaging drugs, and resistance reversal has been observed using c-jun antisense. This preliminary evidence suggests that c-jun may have a role in drug resistance, but additional work with patient tumor samples is required to validate the potential of the JNK pathway as a target.
Vasilevskaya
Irina
I
University of Pennsylvania Cancer Center, 51 N. 39th Street, MAB-103, Philadelphia, PA 19014, USA.
O'Dwyer
Peter J
PJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D016755:Proto-Oncogene Proteins c-jun; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases