Oncol Rep. 2014 May;31(5):2429-37. doi: 10.3892/or.2014.3082. Epub 2014 Mar 12.
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.
Kim JE1, Lee JI1, Jin DH2, Lee WJ3, Park GB4, Kim S4, Kim YS4, Wu TC5, Hur DY4, Kim D4.
Department of Anatomy, Chung-Ang University, College of Medicine, Seoul, Republic of Korea.
Institute for Innovate Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Department of Anatomy, Seoul National University, College of Medicine, Seoul, Republic of Korea.
Department of Anatomy and Laboratory for Cancer Immunotherapy, Inje University, College of Medicine, Busan, Republic of Korea.
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
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.