Clock gene mouse period2 overexpression inhibits growth of human pancreatic cancer cells and has synergistic effect with cisplatin.
Circadian rhythms are the daily oscillations of multiple biological processes regulated by an endogenous clock. The Period2 gene is essential in controlling the circadian rhythm and plays an important role in tumor suppression. We examined whether the overexpression of the mouse Period2 gene (mPer2) in cultured tumor cells from human tissues inhibits cell growth, using the recombinant adenovirus vector AdmPer2. The overexpression of mPer2 in human pancreatic cancer cells (Panc1, Aspc1) reduced cellular proliferation and induced apoptotic cell death. Infection with AdmPer2 also inhibited cell-cycle progression, inducing arrest at the G(2)-M phase. Western blotting analyses confirmed that infection with AdmPer2 reduced Bcl-X(L), Cdc2 and cyclin B1 protein, whereas it increased Bax protein in Aspc1 cells. The overexpression of mPer2 suppressed Cdc2 kinase activity. Moreover, infection with AdmPer2 resulted in dose-dependent synergic cell killing effects with the anticancer agent cisplatin (CDDP) in human pancreatic cancer cells. This synergic effect might be related to the reduction of Bcl-X(L) induced by infection with AdmPer2. Our results suggest that the circadian gene Period2 may play an important role in suppression of cell proliferation in human cancer, and additionally Period2 gene expression level may influence the sensitivity to cisplatin depending on Bcl-X(L) expression level.
Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, 980-8574, Japan.
Akira
A
Oda
Yu
Y
Katayose
Shinichi
S
Yabuuchi
Kuniharu
K
Yamamoto
Masamichi
M
Mizuma
Satoru
S
Shirasou
Toru
T
Onogawa
Hideo
H
Ohtsuka
Hiroshi
H
Yoshida
Hiroki
H
Hayashi
Toshiki
T
Rikiyama
Hyunjung
H
Kim
Youngshik
Y
Choe
Kyungjin
K
Kim
Hosun
H
Son
Fuyuhiko
F
Motoi
Shinichi
S
Egawa
Michiaki
M
Unno
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use*; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D056950:Period Circadian Proteins; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D002945:Cisplatin