Stress hormones mediate drug resistance to paclitaxel in human breast cancer cells through a CDK-1-dependent pathway.
Chemotherapy comprises part of successful treatment regimens for breast cancer, however, up to 50% of patients develop resistance. Stress in cancer patients can equate to poor chemotherapeutic responses. We hypothesize that drug resistance may be associated with stress hormone-induced alterations in breast cancer cells. To test this hypothesis, MDA-MB-231 cells were cultured with paclitaxel and/or cortisol, norepinephrine and epinephrine and cytotoxicity, cell cycle analyses, genomic and proteomic analyses were performed. Paclitaxel-mediated cytotoxicity and G2/M cell cycle arrest were reversed significantly by stress hormones. Genomic and proteomic analyses revealed that stress hormones modulated beta-tubulin isotypes and significantly altered genes and proteins involved in regulation of the G2/M transition, including cyclin-dependent kinase-1 (CDK-1). Inhibition of CDK-1 abrogated stress hormone-mediated reversal of paclitaxel-induced cytotoxicity, indicating that the protective effect of stress hormones act through a CDK-1-dependent mechanism. These data demonstrate that stress hormones interfere with paclitaxel efficacy and contribute significantly to drug resistance.
Flint
Melanie S
MS
Department of Pharmacology & Chemical Biology, Pittsburgh, PA 15213, United States. flintms@upmc.edu
Kim
Grace
G
Hood
Brian L
BL
Bateman
Nicholas W
NW
Stewart
Nicolas A
NA
Conrads
Thomas P
TP
D015075:2-Aminopurine / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000502:physiology*; D004837:Epinephrine / Q000494:pharmacology*; D005260:Female; D023281:Genomics / Q000379:methods; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology*; D009638:Norepinephrine / Q000494:pharmacology*; D017239:Paclitaxel / Q000494:pharmacology*; D040901:Proteomics / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
C469937:N(2)-(2-aminocyclohexyl)-N(6)-(3-chlorophenyl)-9-ethyl-9H-purine-2,6-diamine; D015075:2-Aminopurine; D016203:CDC2 Protein Kinase; D017239:Paclitaxel; D006854:Hydrocortisone; D009638:Norepinephrine; D004837:Epinephrine