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CITED2 is a transcriptional modulator which has been implicated in human oncogenesis. In the present study, we examined whether CITED2 is also involved in the resistance of cancer cells to the chemotherapeutic drug cisplatin. We first observed that knockdown of CITED2 using short-hairpin RNA sensitized non-tumorigenic HEK293 cells to cisplatin. Sensitization to cisplatin following knockdown of CITED2 was also observed in cervical carcinoma HeLa cells and in cisplatin-resistant HeLa cells, thereby showing that acquired cisplatin resistance could be reversed by CITED2 knockdown. This sensitization response was dependent on the status of p53 since efficient sensitization was observed in p53-positive hepatocellular carcinoma (HCC) Sk-Hep-1 cells, whereas a negligible response was produced in the two p53-defective cell lines HCC Mahlavu and lung cancer H1299. In contrast, overexpression of CITED2 decreased sensitivity of HEK293 cells to cisplatin, while moderate resistance was produced in HeLa cells. Overexpression of CITED2 also decreased sensitivity to cisplatin in p53-defective H1299 cells when exogenous p53 expression was re-introduced. We observed that knockdown of CITED2-induced CBP/p300-mediated p53 acetylation (Lys373) in HEK293 cells, thereby leading to a decrease of p53 ubiquitination and subsequent accumulation of the p53 protein. Notably, the effects of CITED2 knockdown on p53 accumulation and the increase of p53's target Bax were more pronounced after treatment with cisplatin. Based on these results, we propose that a combination of cisplatin and CITED2 shRNA may represent an effective treatment against p53-sensitive cancer cells.

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1. Cardiotoxin (CTX) III is a basic polypeptide with 60 amino acid residues isolated from Naja naja atra venom. This is the first report on the mechanism of the anticancer effect of CTX III on human leukaemia K562 cells. 2. Cardiotoxin III was found to inhibit the growth of K562 cells in a time- and dose-dependent manner, with an IC(50) value of 1.7 mug/mL, and displayed several features of apoptosis, including apoptotic body formation, an increase in the sub-G(1) population, DNA fragmentation and poly (ADP-ribose) polymerase (PARP) cleavage. 3. Investigation of the mechanism of CTX III-induced apoptosis revealed that treatment of K562 cells with CTX III resulted in the loss of mitochondrial membrane potential, cytochrome c release from mitochondria into the cytosol and activation of caspase-9 and caspase-3 and the subsequent cleavage of the caspase-3 substrate PARP; however, CTX III did not generate reactive oxygen species (ROS). 4. Taken together, the results indicate that CTX III induces apoptosis in K562 cells through an ROS-independent mitochondrial dysfunction pathway.