title: Serum-nutrient starvation induces cell death mediated by Bax and Puma that is counteracted by p21 and unmasked by Bcl-x(L) inhibition.
abstract: The cyclin-dependent kinase inhibitor p21 (p21WAF1/Cip1) is a multifunctional protein known to promote cell cycle arrest and survival in response to p53-dependent and p53 independent stimuli. We herein investigated whether and how it might contribute to the survival of cancer cells that are in low-nutrient conditions during tumour growth, by culturing isogenic human colorectal cancer cell lines (HCT116) and breast cancer cell lines in a medium deprived in amino acids and serum. We show that such starvation enhances, independently from p53, the expression of p21 and that of the pro-apoptotic BH3-only protein Puma. Under these conditions, p21 prevents Puma and its downstream effector Bax from triggering the mitochondrial apoptotic pathway. This anti-apoptotic effect is exerted from the cytosol but it is unrelated to the ability of p21 to interfere with the effector caspase 3. The survival function of p21 is, however, overcome by RNA interference mediated Bcl-x(L) depletion, or by the pharmacological inhibitor ABT-737. Thus, an insufficient supply in nutrients may not have an overt effect on cancer cell viability due to p21 induction, but it primes these cells to die, and sensitizes them to the deleterious effects of Bcl-x(L) inhibitors regardless of their p53 status.
authors: Centre de Recherche en Cancérologie Nantes Angers, Institut National de la Santé et de la Recherche Médicale UMR 892/Université de Nantes, Nantes, France. frederique.braun@univ-nantes.fr
authors: Frédérique
authors: F
authors: Braun
authors: Joséphine
authors: J
authors: Bertin-Ciftci
authors: Anne-Sophie
authors: AS
authors: Gallouet
authors: Julie
authors: J
authors: Millour
authors: Philippe
authors: P
authors: Juin
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death; D002470:Cell Survival; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000172:deficiency / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D019610:Cytoprotection; D015536:Down-Regulation; D045325:HCT116 Cells; D006801:Humans; D011485:Protein Binding; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D044967:Serum / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism*; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D053148:Caspase 3