title: Tumor suppressor BLU promotes paclitaxel antitumor activity by inducing apoptosis through the down-regulation of Bcl-2 expression in tumorigenesis.
abstract: In this current work, we investigated whether BLU could enhance pro-apoptotic activity of chemotherapeutic drugs in ovarian carcinoma cells. A combination with a chemotherapeutic drug showed an additive effect, and this additive effect was supplemented by the enhancement of caspase-3 and -9 activities. BLU and paclitaxel induced cell cycle arrest in the G2/M phase through the reduction of cyclin dependent kinase 1, cyclin B1, while promoting both p16 and p27 expression. In addition, both BLU and paclitaxel enhanced the expression of the pro-apoptotic protein Bax together with the suppression of anti-apoptotic protein Bcl-2, a protein which is well-known for its function as a regulator in protecting cells from apoptosis. As expected, the Bax and p21 activities were enhanced by BLU or paclitaxel, while a combination of BLU and paclitaxel were additively promoted, whereas Bcl-xL and NF-κB including Bcl-2 activity were inactivated. This study has yielded promising results, which evidence for the first time that BLU could suppress the growth of carcinoma cells. Furthermore, both BLU and paclitaxel inhibited the phosphorylation of signaling components downstream of phosphoinositide 3-kinase, such as 3-phosphoinositide-dependent protein kinase 1, and Akt. Also, BLU plus paclitaxel decreased phosphorylation of p70 ribosomal S6 kinase, as well as decreasing the phosphorylation of glycogen synthase kinase-3β, which is one of the representative targets of the mammalian target of rapamycin signaling cascade. These results provide evidence that BLU enhances G2/M cell cycle arrest and apoptotic cell death through the up-regulation of Bax, p21 and p53 expression.
authors.affiliation: Department of Obstetrics and Gynecology, Kangnam Sacred Heart Hospital, Hallym University, 948-1, Daerim 1-dong, Yeongdeungpo-gu, Seoul 150-950, Republic of Korea.
authors.forename: Sung Taek
authors.initials: ST
authors.lastname: Park
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Byun
authors.forename: Boh-Ram
authors.initials: BR
authors.lastname: Kim
authors.forename: Seung Myung
authors.initials: SM
authors.lastname: Dong
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Park
authors.forename: Pong Rheem
authors.initials: PR
authors.lastname: Jang
authors.forename: Seung Bae
authors.initials: SB
authors.lastname: Rho
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D003598:Cytoskeletal Proteins; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006801:Humans; D015151:Immunoblotting; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D025521:Tumor Suppressor Proteins; C472720:ZMYND10 protein, human; D051020:bcl-X Protein; D008156:Luciferases; D017239:Paclitaxel