| Summary: | 碩士 === 國立陽明大學 === 醫學生物技術研究所 === 91 === Adenovirus-5 early region 1 (E1A) sensitizes different cancer cells to DNA damage agents through different pathways. However, the detail mechanism of E1A-mediated sensitization to chemotherapeutic agents in cancer cells is unclear. Cisplatin is a commonly used DNA-damaging antineoplastic agent. It binds to DNA and causes DNA interstrand cross-link that interferes the repair mechanism, eventually leading to cell death. Both Rb and p53 are mutated in many tumor cells. Recent study showed that Bcl-xL deamidation plays a critical role in cisplatin-induced apoptosis in Rb null cancer cell. Bcl-xL deamidation reverses anti-apoptotic Bcl-xL to apoptotic molecular and Rb suppresses the deamidation of Bcl-xL. It is known that E1A can inactivate Rb normal function by directly binding to Rb. Therefore, we proposed if E1A interrupts Rb function, it should result in the deamidation of Bcl-xL to cisplatin. Our results show that E1A sensitized ovarian cancer cells to cisplatin. Rb was normal in SKOV3.ip1 cells, and E1A interacted with Rb that might block Rb function. E1A-mediated sensitization was correlated to cisplatin-induced Bcl-xL modification. From phosphatase assay, we identified that the modification of Bcl-xL was not due to phosphorylation. Olomoucine is known to block CDK and also blocks Bcl-xL modification. We found that olomoucine suppressed Bcl-xL modification and rendered SKOV3.ip1 E1A cells resistant to cisplatin. In our studies, we prove another mechanism of E1A chemosensitiztion in human ovarian cancer cells. That is, Bcl-xL modification via blocking Rb is involved in E1A-mediated cisplatin sensitization in ovarian cancer cells. In addition, this modification Bcl-xL is likely deamidation.
|
|---|
