Induction of wild-type p53, Bax, and acidic endonuclease during somatostatin-signaled apoptosis in MCF-7 human breast cancer cells.
Somatostatin (SST) analogs inhibit tumor cell growth by exerting direct anti-proliferative effects with cytostatic (growth arrest) or cytotoxic (apoptosis) consequences. The SST analog SMS 201-995 (octreotide, OCT) inhibits growth of MCF-7 human breast adenocarcinoma cells, which express multiple SSTRs. Its action has been reported to result in either apoptosis or growth arrest, but the underlying mechanisms have not been elucidated in this tumor cell model. Here, we report that OCT elicits cytotoxic response in these cells, leading to apoptosis, which is associated with a rapid, time-dependent induction of wild-type p53 and an increase in Bax. There was no G1 cell-cycle arrest in these cells during OCT treatment as suggested by the decrease in G1/S ratio and the lack of induction of pRb and p21. Additionally, we demonstrate that OCT-induced DNA fragmentation in this cell line is due to selective activation of a cation-insensitive acidic endonuclease. Our data provide a rationale for utilizing SST analogs to treat SSTR-positive breast cancer cells expressing wild-type p53.
Sharma
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K
Fraser Laboratories for Diabetes Research, McGill University and Royal Victoria Hospital, Montreal, Quebec, Canada.
Srikant
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CB
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D004273:DNA, Neoplasm / Q000378:metabolism; D004720:Endonucleases / Q000096:biosynthesis*; D016193:G1 Phase / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000378:metabolism; D015282:Octreotide / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D019253:Proto-Oncogene Proteins c-bcl-2; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013004:Somatostatin / Q000031:analogs & derivatives*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*; D051028:bcl-2-Associated X Protein
D018931:Antineoplastic Agents, Hormonal; C494826:BAX protein, human; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D013004:Somatostatin; D004720:Endonucleases; D015282:Octreotide