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.
Constant expression of E6 and E7 mRNA by high-risk human papillomaviruses (HPV) abrogates p53 and retinoblastoma protein function, respectively, and is essential for the development of cervical cancer. Despite E6, some chemotherapy drugs can stabilize p53 in cervical cancer cells. It is not known how chemotherapy-induced p53 activation and cytotoxicity are affected when the amount of E6 mRNA is decreased before the drug treatment. In this study, HPV18-positive HeLa cervical cancer cells were transfected with short interfering RNA (siRNA) molecules targeting HPV18 E6 mRNA before treatment with carboplatin, cisplatin, doxorubicin, etoposide, gemcitabine, mitomycin, mitoxantrone, oxaliplatin, paclitaxel, and topotecan. Transfection with siRNA was followed by nuclear accumulation of p53, but the effect was transient despite continuously suppressed HPV mRNA levels. When treatment with E6 siRNA was coupled with chemotherapy, the p53 activity after treatment with carboplatin and paclitaxel was additively increased, whereas the p53 activation induced by the rest of the drugs was synergistically increased. Treatment with E6 siRNA alone moderately inhibited HeLa cell proliferation but did not induce detectable apoptosis. The combined cytotoxic effect of E6 siRNA and chemotherapy ranged from subadditive to synergistic, depending on the drug. The decrease of E6 mRNA sensitized HeLa cells, for example, to doxorubicin and gemcitabine but counteracted the cytotoxicity of cisplatin and etoposide. In conclusion, activating p53 by degrading E6 mRNA may either increase or decrease the chemosensitivity of cervical cancer cells, depending on the chemotherapy compound.
Koivusalo
Riku
R
Dept. of Obst and Gynecology, Turku University Central Hospital, Kiinamyllynkatu 4-8, 20520 Turku, Finland.
Krausz
Eberhard
E
Helenius
Hans
H
Hietanen
Sakari
S
D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006367:HeLa Cells; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53