Cell cycle regulatory protein 5 (Cdk5) is a novel downstream target of ERK in carboplatin induced death of breast cancer cells.
Neuronal cell specific cyclin-dependent kinase 5 (Cdk5) is a known regulator of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. We report that Cdk5 also plays an important role in the proliferation of breast cancer cells MCF-7 and MDA MB-231 and is functionally involved in chemosensitivity as well as in cell death pathways induced by anti-cancer drug carboplatin (Carb). Here, we demonstrate that carboplatin induced Cdk5 activation under positive regulation of ERK, promotes cell death in MCF-7 and MDA MB-231 cells. DNA-damage stress enhanced ERK activity utilizes Cdk5 as one of its downstream targets for the execution of death signal in carboplatin induced death in MCF-7 and MDA MB-231 cells. Additionally, present data clearly indicates that activated Cdk5 modulates p53 transactivation in MCF-7 cells. However, in p53 mutant MDA MB-231 cells, Cdk5 mediated cell death is likely to be p53 independent. Collectively, our findings not only draw attention to the extra-neuronal functions of Cdk5 but also propose Cdk5 as a novel and potential therapeutic target of chemotherapeutic drugs.
Upadhyay
Ankur Kumar
AK
National Centre for Cell Science, NCCS Complex, Ganeshkhind, Pune, India.
Ajay
Amrendra Kumar
AK
Singh
Sandeep
S
Bhat
Manoj Kumar
MK
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology*; D016190:Carboplatin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D034741:RNA, Small Interfering
D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D016190:Carboplatin; D015500:Chloramphenicol O-Acetyltransferase; D051360:Cyclin-Dependent Kinase 5; D048049:Extracellular Signal-Regulated MAP Kinases