The PIM1 kinase is a critical component of a survival pathway activated by docetaxel and promotes survival of docetaxel-treated prostate cancer cells.
A defining characteristic of solid tumors is the capacity to divide aggressively and disseminate under conditions of nutrient deprivation, limited oxygen availability, and exposure to cytotoxic drugs or radiation. Survival pathways are activated within tumor cells to cope with these ambient stresses. We here describe a survival pathway activated by the anti-cancer drug docetaxel in prostate cancer cells. Docetaxel activates STAT3 phosphorylation and transcriptional activity, which in turns induces expression of the PIM1 gene, encoding a serine-threonine kinase activated by many cellular stresses. Expression of PIM1 improves survival of docetaxel-treated prostate cancer cells, and PIM1 knockdown or expression of a dominant-negative PIM1 protein sensitize cells to the cytotoxic effects of docetaxel. PIM1 in turn mediates docetaxel-induced activation of NFkappaB transcriptional activity, and PIM1 depends in part on RELA/p65 proteins for its prosurvival effects. The PIM1 kinase plays a critical role in this STAT3 --> PIM1 --> NFkappaB stress response pathway and serves as a target for intervention to enhance the therapeutic effects of cytotoxic drugs such as docetaxel.
Zemskova
Marina
M
Center for Health Disparities and Molecular Medicine, Departments of Medicine and Microbiology, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA.
Sahakian
Eva
E
Bashkirova
Svetlana
S
Lilly
Michael
M
D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D000077143:Docetaxel; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000737:chemistry / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology*; D014158:Transcription, Genetic
D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D043823:Taxoids; D000077143:Docetaxel; D051573:Proto-Oncogene Proteins c-pim-1