Specific apoptosis induction in human papillomavirus-positive cervical carcinoma cells by photodynamic antisense regulation.
Human papillomavirus type 18 (HPV18) is frequently detected in cervical cancer cells. The viral proteins E6 and E7 are expressed consistently and have oncogenic activities. The E7 protein binds to a tumor suppressor, the retinoblastoma gene product (pRB), however, leading to the stabilization of tumor suppressor, p53 protein. On the other hand, another viral product, E6, forms complexes with p53 and abrogates its function, resulting in tumor progression. These facts imply that the E6 oncogene is one of the ideal targets for directed gene therapy in HPV-positive cervical cancer. In this study, we tried photodynamic antisense regulation of the antiapoptotic E6 expression using a photocross-linking reagent, 4,5',8-trimethylpsoralen, conjugated oligo(nucleoside phosphorothioate) (Ps-S-Oligo). This photodynamic antisense strategy effectively elicited the apoptotic death of HPV18-positive cervical cancer cells through the selective repression of E6 mRNA and consequent stabilization of p53 protein. E7-mediated signals potentially activated the p53 function and mobilized the p53 pathway to deliver pro-apoptotic signals to the cancer cells, leading to the suppression of in vivo tumorigenesis. An extremely low concentration of cisplatin in addition to Ps-S-Oligos further up-regulated p53 activity, provoking massive apoptotic induction. These results suggest that the photodynamic antisense strategy has the great therapeutic potential in HPV-positive cervical cancers.
Yamayoshi
Asako
A
Department of Molecular Genetics, Division of Molecular and Cell Therapeutics, Kyushu University, Maidashi, Fukuoka 812-8582, Japan.
Kato
Kiyoko
K
Suga
Shin
S
Ichinoe
Akimasa
A
Arima
Takahiro
T
Matsuda
Takao
T
Kato
Hidenori
H
Murakami
Akira
A
Wake
Norio
N
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002277:Carcinoma / Q000188:drug therapy* / Q000821:virology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016373:DNA, Antisense / Q000737:chemistry / Q000627:therapeutic use*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D005260:Female; D052161:Human papillomavirus 18; D006801:Humans; D051379:Mice; D009856:Oncogene Proteins, Viral / Q000037:antagonists & inhibitors* / Q000235:genetics; D017319:Photosensitizing Agents / Q000737:chemistry / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D013873:Thionucleotides / Q000737:chemistry / Q000627:therapeutic use; D014307:Trioxsalen / Q000737:chemistry / Q000627:therapeutic use*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000821:virology
D016373:DNA, Antisense; D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; C052633:E7 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; D017319:Photosensitizing Agents; D012333:RNA, Messenger; D013873:Thionucleotides; D016159:Tumor Suppressor Protein p53; D014307:Trioxsalen