This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Koivusalo, R. Articles by Hietanen, S. Search for Related Content PubMed PubMed Citation Articles by Koivusalo, R. Articles by Hietanen, S.

Chemoradiation of Cervical Cancer Cells

Targeting Human Papillomavirus E6 and p53 Leads to Either Augmented or Attenuated Apoptosis Depending on the Platinum Carrier Ligand¹

Department of Obstetrics and Gynecology [R. K., S. H.], and Department of Oncology [P. R.], Turku University Central Hospital, 20520 Turku, Finland; Medicity Research Laboratory [R. K., S. H.], and Department of Biostatistics [H. H.], University of Turku, 20520 Turku, Finland; and Cyclacel Ltd, Dundee, DD1 5JJ Scotland, United Kingdom [E. K.]

Recent clinical trials comparing concurrent chemotherapy and radiation with radiation alone in cervical cancer have shown that chemoradiation reduces the risk of death by 30–50%. Despite the clinical success, treatment responses at the cellular level are still inadequately explored. A key event in cervical carcinogenesis is the disruption of p53 tumor suppressor pathway by human papillomavirus (HPV) E6 oncogene. We found that regardless of the HPV type in SiHa (HPV 16+) CaSki (HPV 16+), HeLa (HPV 18+), and UT-DEC-1 (HPV 33+) cell lines, cisplatin, carboplatin, and a novel platinum compound, oxaliplatin, activated a p53 reporter and reduced the HPV E6 mRNA. Carboplatin and oxaliplatin treatment led also to stabilization of p53, whereas none of the platinums changed p73 levels. After irradiation (IR) alone, a decrease in HPV E6 mRNA levels and an activation of the p53-reporter were detected in SiHa, CaSki, and HeLa cells, but not in UT-DEC-1 cells. Concomitant platinum treatment and IR led to poly(ADP-ribose) polymerase cleavage as a sign of caspase-3 activation and apoptosis. Clonogenic survival was enhanced by expressing a dominant negative p53 or ectopic HPV16 E6 in SiHa and HeLa cells treated with IR, carboplatin, or oxaliplatin or with a combination of IR + carboplatin or oxaliplatin. In contrast, dominant negative p53 or ectopic HPV 16 E6 sensitized the cells to cisplatin. Pt chemotherapeutics and radiation had a synergistic cytotoxic effect as determined by Bliss independence criterion. Taken together, p53 has a significant role in the cellular response to chemoradiation treatment in cervical cancer cell lines, but p53 activity may have a dramatically different effect on cell survival depending on the platinum carrier ligand.

This article has been cited by other articles:

				S. Nemoto, M. Nakamura, Y. Osawa, S. Kono, Y. Itoh, Y. Okano, T. Murate, A. Hara, H. Ueda, Y. Nozawa, et al. Sphingosine Kinase Isoforms Regulate Oxaliplatin Sensitivity of Human Colon Cancer Cells through Ceramide Accumulation and Akt Activation J. Biol. Chem., April 17, 2009; 284(16): 10422 - 10432. [Abstract] [Full Text] [PDF]

				R. Koivusalo, A. Mialon, H. Pitkanen, J. Westermarck, and S. Hietanen Activation of p53 in Cervical Cancer Cells by Human Papillomavirus E6 RNA Interference Is Transient, but Can Be Sustained by Inhibiting Endogenous Nuclear Export-Dependent p53 Antagonists Cancer Res., December 15, 2006; 66(24): 11817 - 11824. [Abstract] [Full Text] [PDF]

				S. S. Liu, K. Y.-K. Chan, R. C.-Y. Leung, H. K.-W. Law, T.-W. Leung, and H. Y.-S. Ngan Enhancement of the radiosensitivity of cervical cancer cells by overexpressing p73{alpha} Mol. Cancer Ther., May 1, 2006; 5(5): 1209 - 1215. [Abstract] [Full Text] [PDF]

				S. C. Kaul, S. Aida, T. Yaguchi, K. Kaur, and R. Wadhwa Activation of Wild Type p53 Function by Its Mortalin-binding, Cytoplasmically Localizing Carboxyl Terminus Peptides J. Biol. Chem., November 25, 2005; 280(47): 39373 - 39379. [Abstract] [Full Text] [PDF]

				R. Koivusalo, E. Krausz, H. Helenius, and S. Hietanen Chemotherapy Compounds in Cervical Cancer Cells Primed by Reconstitution of p53 Function after Short Interfering RNA-Mediated Degradation of Human Papillomavirus 18 E6 mRNA: Opposite Effect of siRNA in Combination with Different Drugs Mol. Pharmacol., August 1, 2005; 68(2): 372 - 382. [Abstract] [Full Text] [PDF]

				J. Boyer, E. G. McLean, S. Aroori, P. Wilson, A. McCulla, P. D. Carey, D. B. Longley, and P. G. Johnston Characterization of p53 Wild-Type and Null Isogenic Colorectal Cancer Cell Lines Resistant to 5-Fluorouracil, Oxaliplatin, and Irinotecan Clin. Cancer Res., March 15, 2004; 10(6): 2158 - 2167. [Abstract] [Full Text] [PDF]