Inhibition of p53 sensitizes MCF-7 cells to ceramide treatment.
Ceramide signaling plays an important role in tumor progression and development of chemoresistance, and ceramide-based therapies are proposed as potential therapeutic tools for the treatment of breast cancer. We investigated the effect of exogenous ceramide on the cell cycle progression of MCF-7 breast cancer cells. Ceramide induced a selective arrest of MCF-7 cells in the G1-phase, which was associated with a decreased expression of cyclins D and E and increased expression of p53 and p21. Interestingly, inhibition of p53 using pifithrin alpha or RNAi sensitized MCF-7 cells to ceramide-induced cell death. DNA content analysis suggested that sensitization of cells was due to an increased induction of apoptosis in MCF-7 cells. The increased sensitivity to ceramide, in the context of p53 inhibition, may be due to decreased expression of p21, as siRNA targeted to p21 also sensitized MCF-7 cells to ceramide-induced death. These data demonstrate that in tumors with inactivating mutations of p53, ceramide-based therapies might provide a novel and effective treatment option.
Department of Pharmacology and Experimental Therapeutics, LSU Health Sciences Center, New Orleans, LA 70112, USA.
Amanda P
AP
Struckhoff
Bhumi
B
Patel
Barbara S
BS
Beckman
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D052160:Benzothiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002518:Ceramides / Q000008:administration & dosage / Q000494:pharmacology*; D056741:Cyclin D / Q000235:genetics; D019927:Cyclin E / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000494:pharmacology*; D014050:Toluene / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000235:genetics
C417740:2-octadecanoylamino-1,3-dihydroxy-octadecene-4; D052160:Benzothiazoles; D002518:Ceramides; D056741:Cyclin D; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D014050:Toluene; C121565:pifithrin