Human papillomavirus E6 and E7 oncoproteins alter cell cycle progression but not radiosensitivity of carcinoma cells treated with low-dose-rate radiation
| Autor: | William G. Nelson, Jonathan C. Walsh, Theodore L. DeWeese, Kathleen R. Cho, Larry E. Dillehay, Theodore D. Kessis, Lora Hedrick |
|---|---|
| Rok vydání: | 1997 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
G2 Phase Cancer Research Cell cycle checkpoint Papillomavirus E7 Proteins medicine.medical_treatment Cell Radiation Dosage Radiation Tolerance Cyclins Tumor Cells Cultured medicine Humans Radiology Nuclear Medicine and imaging Radiosensitivity Radiation business.industry G1 Phase Oncogene Proteins Viral Cell cycle Repressor Proteins Radiation therapy medicine.anatomical_structure Oncology Cell culture Colonic Neoplasms Cancer cell Immunology Cancer research Tumor Suppressor Protein p53 business DNA Damage |
| Zdroj: | International Journal of Radiation Oncology*Biology*Physics. 37:145-154 |
| ISSN: | 0360-3016 |
| DOI: | 10.1016/s0360-3016(96)00448-8 |
| Popis: | Purpose: Low-dose-rate radiation therapy has been widely used in the treatment of urogenital malignancies. When continuously exposed to low-dose-rate ionizing radiation, target cancer cells typically exhibit abnormalities in replicative cell-cycle progression. Cancer cells that arrest in the G2 phase of the cell cycle when irradiated may become exquisitely sensitive to killing by further low-dose-rate radiation treatment. Oncogenic human papillomaviruses (HPVs), which play a major role in the pathogenesis of uterine cervix cancers and other urogenital cancers, encode E6 and E7 transforming proteins known to abrogate a p53-dependent G1 cell-cycle checkpoint activated by conventional acute-dose radiation exposure. This study examined whether expression of HPV E6 and E7 oncoproteins by cancer cells alters the cell-cycle redistribution patterns accompanying low-dose-rate radiation treatment, and whether such alteraitons in cell-cycle redistribution affect cancer cell killing. Methods and Materials: RKO carcinoma cells, which contain wild-type P53 alleles, and RKO cell sublines genetically engineered to express HPV E6 and E7 oncoproteins, were treated with low-dose-rate (0.25-Gy/h) radiation and then assessed for p53 and p21WAF1/CIP1 polypeptide induction by immunoblot analysis, for cell-cycle redistribution by flow cytometry, and for cytotoxicity by clonogenic survival assay. Results: Low-dose-rate radiation of RKO carcinoma cells triggered p53 polypeptide elevations, p21WAF1/CIP1 induction, and arrest in the G1 and G2 phases of the cell cycle. In contrast, RKO cells expressing E6 and E7 transforming proteins from high-risk oncogenic HPVs (HPV 16) arrested in G2, but failed to arrest in G1, when treated with low-dose-rate ionizing radiation. Abrogation of the G1 cell-cycle checkpoint activated by low-dose-rate radiation exposure appeared to be a characteristic feature of transforming proteins from high-risk oncogenic HPVs: RKO cells expressing E6 from a low-risk nononcogenic HPV (HPV 11) exposed to low-dose-rate radiation arrested in both G1 and G2. Surprisingly, despite differences in cell-cycle redistribution accompanying low-dose-rate radiation treatment associated with high-risk HPV transforming protein expression, no consistent differences in clonogenic survival following low-dose-rate radiation treatment were found for RKO cell sublines expressing high-risk HPV oncoproteins and arresting only in G2 during low-dose-rate radiation exposure vs. RKO cell sublines exhibiting both G1 and g2 cell-cycle arrest when irradiated. Conclusion: The results of this study demonstrate that neither HPV oncoprotein expression nor loss of the radiation-activated G1 cell-cycle checkpoint alter the sensitivity of RKO carcinoma cell lines to low-dose-rate radiation exposure in vitro . Perhaps for urogenital malignancies associated with oncogenic HPVs in vitro , HPV oncoprotein-mediated abrogation of the G1 cell-cycle checkpoint may not limit the efficacy of low-dose-rate radiation therapy. |
| Databáze: | OpenAIRE |
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