title: Sequential treatment of HPV E6 and E7-expressing TC-1 cells with bortezomib and celecoxib promotes apoptosis through p-p38 MAPK-mediated downregulation of cyclin D1 and CDK2.
abstract: Interruption of the cell cycle is accompanied by changes in several related molecules that result in the activation of apoptosis. The present study was performed to verify the apoptotic effects of sequential treatment with bortezomib and celecoxib in TC-1 cells expressing the human papillomavirus (HPV) E6 and E7 proteins. In TC-1 cells sequentially treated with bortezomib and celecoxib, apoptosis was induced through decreased expression of signal transducer and activator of transcription-3 (STAT3), cyclin D1 and cyclin-dependent kinase (CDK) 2, which are major regulators of the G0/G1 cell cycle checkpoint. In addition, increased levels of p21, CHOP, BiP and p-p38 MAPK were identified in these cells. The treatment-induced apoptosis was effectively inhibited by treatment with SB203580, an inhibitor of p-p38. Moreover, the growth of tumors sequentially treated with bortezomib and celecoxib was retarded compared to the growth of tumors exposed to a single treatment with either bortezomib or celecoxib in vivo. We demonstrated that sequential treatment with bortezomib and celecoxib induced apoptosis via p-p38-mediated G0/G1 cell cycle arrest and endoplasmic reticulum (ER) stress. Sequential treatment with these two drugs could therefore be a useful therapy for cervical cancer.
authors.affiliation: Department of Anatomy, Chung-Ang University, College of Medicine, Seoul, Republic of Korea.
authors.forename: Jee-Eun
authors.initials: JE
authors.lastname: Kim
authors.affiliation: Department of Anatomy, Chung-Ang University, College of Medicine, Seoul, Republic of Korea.
authors.forename: Ji-In
authors.initials: JI
authors.lastname: Lee
authors.affiliation: Institute for Innovate Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Dong-Hoon
authors.initials: DH
authors.lastname: Jin
authors.affiliation: Department of Anatomy, Seoul National University, College of Medicine, Seoul, Republic of Korea.
authors.forename: Wang Jae
authors.initials: WJ
authors.lastname: Lee
authors.affiliation: Department of Anatomy and Laboratory for Cancer Immunotherapy, Inje University, College of Medicine, Busan, Republic of Korea.
authors.forename: Ga Bin
authors.initials: GB
authors.lastname: Park
authors.affiliation: Department of Anatomy and Laboratory for Cancer Immunotherapy, Inje University, College of Medicine, Busan, Republic of Korea.
authors.forename: Seonghan
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Laboratory for Cancer Immunotherapy, Inje University, College of Medicine, Busan, Republic of Korea.
authors.forename: Yeong Seok
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
authors.affiliation: Department of Anatomy and Laboratory for Cancer Immunotherapy, Inje University, College of Medicine, Busan, Republic of Korea.
authors.forename: Dae Young
authors.initials: DY
authors.lastname: Hur
authors.affiliation: Department of Anatomy and Laboratory for Cancer Immunotherapy, Inje University, College of Medicine, Busan, Republic of Korea.
authors.forename: Daejin
authors.initials: D
authors.lastname: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D000068579:Celecoxib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000096:biosynthesis*; D051357:Cyclin-Dependent Kinase 2 / Q000096:biosynthesis*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015536:Down-Regulation; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis; D050725:Papillomavirus E7 Proteins / Q000096:biosynthesis; D011719:Pyrazines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D012097:Repressor Proteins / Q000096:biosynthesis; D050796:STAT3 Transcription Factor / Q000096:biosynthesis; D013449:Sulfonamides / Q000494:pharmacology*; D051742:Transcription Factor CHOP / Q000096:biosynthesis; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; C530105:Ccnd1 protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D052246:Cyclooxygenase 2 Inhibitors; C497250:Ddit3 protein, mouse; C068651:E6 protein, Human papillomavirus type 16; D007093:Imidazoles; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D011719:Pyrazines; D011720:Pyrazoles; D011725:Pyridines; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D013449:Sulfonamides; C059731:oncogene protein E7, Human papillomavirus type 16; D019938:Cyclin D1; D051742:Transcription Factor CHOP; D000069286:Bortezomib; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D048051:p38 Mitogen-Activated Protein Kinases; D000068579:Celecoxib; C093642:SB 203580