title: The PI3 kinase inhibitor NVP-BKM120 induces GSK3/FBXW7-dependent Mcl-1 degradation, contributing to induction of apoptosis and enhancement of TRAIL-induced apoptosis.
abstract: This study focuses on determining whether and how the novel PI3 kinase inhibitor NVP-BKM120 (BKM120) induces apoptosis and enhances TRAIL-induced apoptosis in human lung cancer cells. We found that BKM120 reduced Mcl-1 levels across the tested cell lines along with induction of apoptosis and enhancement of TRAIL-induced apoptosis. Enforced expression of ectopic Mcl-1 significantly attenuated the effects of BKM120 alone or in combination with TRAIL on induction of apoptosis. Thus Mcl-1 downregulation contributes to BKM120-induced apoptosis or enhancement of TRAIL-induced apoptosis. Moreover, we have demonstrated that BMK120 decreases Mcl-1 levels through facilitating its degradation involving a GSK3/FBXW7-dependent mechanism.
authors.affiliation: Department of Respiration, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Ren
authors.forename: Liqun
authors.initials: L
authors.lastname: Zhao
authors.forename: Yikun
authors.initials: Y
authors.lastname: Li
authors.forename: Ping
authors.initials: P
authors.lastname: Yue
authors.forename: Xingming
authors.initials: X
authors.lastname: Deng
authors.forename: Taofeek K
authors.initials: TK
authors.lastname: Owonikoko
authors.forename: Mingwei
authors.initials: M
authors.lastname: Chen
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.forename: Shi-Yong
authors.initials: SY
authors.lastname: Sun
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004357:Drug Synergism; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009025:Morpholines / Q000494:pharmacology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000631:Aminopyridines; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C579095:MCL1 protein, human; D009025:Morpholines; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C571178:NVP-BKM120; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D044767:Ubiquitin-Protein Ligases; D058539:Phosphatidylinositol 3-Kinase; D038362:Glycogen Synthase Kinase 3
keywords: Apoptosis; BKM120; Lung cancer; PI3 kinase; TRAIL
references.citation: Curr Opin Pharmacol. 2004 Aug;4(4):333-9
references.pmid: 15251125
references.citation: Clin Cancer Res. 2012 Jan 1;18(1):184-95
references.pmid: 22065080
references.citation: Rev Recent Clin Trials. 2009 Jan;4(1):34-41
references.pmid: 19149761
references.citation: Nature. 2004 Dec 9;432(7018):775-9
references.pmid: 15592418
references.citation: Cancer Gene Ther. 2005 Mar;12(3):228-37
references.pmid: 15550937
references.citation: Mol Cancer Ther. 2012 Aug;11(8):1747-57
references.pmid: 22653967
references.citation: Cell Death Differ. 2010 Aug;17(8):1288-301
references.pmid: 20168333
references.citation: J Immunol. 2010 Mar 15;184(6):3213-22
references.pmid: 20173022
references.citation: Clin Cancer Res. 2009 Jan 1;15(1):150-9
references.pmid: 19118042
references.citation: J Thorac Cardiovasc Surg. 2006 Dec;132(6):1356-62
references.pmid: 17140955
references.citation: Biochem Biophys Res Commun. 2001 Jan 26;280(3):788-97
references.pmid: 11162590
references.citation: FEBS Lett. 2010 Jul 16;584(14):2981-9
references.pmid: 20540941
references.citation: Cancer Lett. 2013 May 28;332(2):141-50
references.pmid: 21071136
references.citation: Cancer Res. 1997 Nov 1;57(21):4931-9
references.pmid: 9354460
references.citation: Apoptosis. 2005 Dec;10(6):1411-8
references.pmid: 16215673
references.citation: Nature. 2011 Mar 3;471(7336):110-4
references.pmid: 21368834
references.citation: Mol Cancer Ther. 2012 Feb;11(2):317-28
references.pmid: 22188813
references.citation: J Natl Cancer Inst. 2004 Dec 1;96(23):1769-80
references.pmid: 15572759
references.citation: J Mol Med (Berl). 2012 Jun;90(6):695-706
references.pmid: 22207485
references.citation: Cancer Res. 2008 Apr 15;68(8):2944-51
references.pmid: 18413764
references.citation: J Pediatr Surg. 2004 Apr;39(4):516-21
references.pmid: 15065019
references.citation: Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):9085-90
references.pmid: 15150404
references.citation: J Clin Invest. 2008 Jun;118(6):1979-90
references.pmid: 18523647
references.citation: Science. 2002 Feb 1;295(5556):868-72
references.pmid: 11786607
references.citation: Mol Cancer Ther. 2008 Aug;7(8):2339-47
references.pmid: 18723481
references.citation: Expert Opin Ther Targets. 2010 Oct;14(10):1091-108
references.pmid: 20819019
references.citation: Cancer Biol Ther. 2008 Feb;7(2):163-73
references.pmid: 18059181
references.citation: Nature. 2000 Oct 12;407(6805):770-6
references.pmid: 11048727
references.citation: Haematologica. 2012 Jan;97(1):38-46
references.pmid: 21933852
references.citation: Cancer Res. 2008 Aug 1;68(15):6271-80
references.pmid: 18676851
references.citation: Clin Exp Pharmacol Physiol. 2004 Mar;31(3):119-28
references.pmid: 15008953
references.citation: Mol Cancer Ther. 2008 May;7(5):1156-63
references.pmid: 18483303
references.citation: Cancer Cell. 2007 Jul;12(1):66-80
references.pmid: 17613437
references.citation: J Neurosci. 2001 Dec 15;21(24):9519-28
references.pmid: 11739563
references.citation: Apoptosis. 2005 Dec;10(6):1203-10
references.pmid: 16215675
references.citation: J Clin Oncol. 2012 Jan 20;30(3):282-90
references.pmid: 22162589
references.citation: Cancer Sci. 2006 Oct;97(10):1093-8
references.pmid: 16984382
references.citation: Cell Death Differ. 2004 Oct;11(10):1084-91
references.pmid: 15243584
references.citation: Clin Cancer Res. 2011 May 15;17(10):3233-47
references.pmid: 21355080
references.citation: Nature. 2011 Mar 3;471(7336):104-9
references.pmid: 21368833
references.citation: J Biol Chem. 2003 Dec 19;278(51):51606-12
references.pmid: 14563837
references.citation: Surgery. 2005 Aug;138(2):391-7
references.pmid: 16153452
references.citation: Apoptosis. 2012 May;17(5):503-15
references.pmid: 22246639
references.citation: J Biol Chem. 2008 Nov 7;283(45):30540-8
references.pmid: 18765672
references.citation: Cancer Res. 2011 Jan 1;71(1):154-63
references.pmid: 21084267
references.citation: Oncogene. 1999 Apr 8;18(14):2357-65
references.pmid: 10327056