Cisplatin is one of the most potent anti-tumor agents, which displays clinical activity against a wide variety of solid tumors. The anti-neoplastic activity of cisplatin results from cisplatin- induced DNA damage, which further triggers cellular apoptosis. However, the effective use of cisplatin is limited by the development of cisplatin resistance in cancer cells. Damaged DNA binding protein (DDB2) has been reported to be able to bind UV- or cisplatin-induced DNA damage, and believed to have a correlation with the apoptotic event, especially the apoptosis induced by DNA damaging agents. However, the relationship between DDB2 and cisplatin- induced apoptosis needs to be validated and the mechanism needs to be explored. The specific hypothesis addressed in this proposal is that DDB2 mediates cisplatin-induced apoptosis through binding DNA damage to relay the apoptotic signals, and regulating pro- and anti-apoptotic proteins;as a result, DDB2 deficiency confers cancer cells resistance to cisplatin. The proposed work will utilize relevant biochemical, biophysical, immunological, cellular and molecular technologies mostly established and ongoing in the PI's laboratory to address the following specific aims: (1) To validate the role of DDB2 in cisplatin-induced apoptosis and the relationship between DDB2 and Bcl-2 in varying cancer cell lines and human tumor tissues;(2) To define the role of DDB2 recognition of cisplatin-induced DNA damage in triggering apoptosis;(3) To delineate the mechanism through which DDB2 down-regulates Bcl-2 level;(4) To reveal the relationship between DDB2 and p53 in the cisplatin-induced apoptosis;(5) To test the role of DDB2 in cisplatin sensitivity and cisplatin- induced apoptosis in vivo. The experimental focus of this proposal is on the relationship between DDB2 and apoptosis. Thus, the above-mentioned specific aims are designed to provide a comprehensive assessment of the regulatory function of DDB2 on cisplatin-induced apoptosis and the development of cisplatin resistance.
Cisplatin was first described as an anti-tumor agent in 1965 by Rosenberg. It has been in widespread clinical use for more than three decades to treat various malignant tumors. However, many human tumors have either intrinsic resistance to cisplatin or acquire resistance after the initial patient treatment. This has become a major problem limiting its effective use. Cisplatin kills tumor cells through interaction with cellular DNA and damaging it. The damaged DNA triggers programmed cell death pathway (apoptosis), and finally commits cancer cells to suicide. However, the cisplatin-resistant cancer cells hardly undergo apoptosis after cisplatin treatment due to multi-reasons. We have identified one protein, named damaged DNA binding protein 2 (DDB2), which can mediate cisplatin-induced apoptosis. In this proposal, we will further define how DDB2 facilitates cisplatin-induced programmed cell death in cisplatin-resistant cancer cells and how DDB2 sensitizes cisplatin-resistant tumors to cisplatin treatment. Ultimately, we hope to translate this knowledge into new strategies for increasing the cisplatin sensitivity and treating recalcitrant tumors.
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