Cisplatin is one of the most effective anticancer agents widely used in the treatment of solid tumors. It is generally considered as a cytotoxic drug which kills cancer cells by damaging DNA and inhibiting DNA synthesis. How cells respond to cisplatin-induced DNA damage plays a critical role in deciding cisplatin sensitivity. Cisplatin-induced DNA damage activates various signaling pathways to prevent or promote cell death. This paper summarizes our current understandings regarding the mechanisms by which cisplatin induces cell death and the bases of cisplatin resistance. We have discussed various steps, including the entry of cisplatin inside cells, DNA repair, drug detoxification, DNA damage response, and regulation of cisplatin-induced apoptosis by protein kinases. An understanding of how various signaling pathways regulate cisplatin-induced cell death should aid in the development of more effective therapeutic strategies for the treatment of cancer.

The inhibitor of κ B kinase-ε (IKKε), a breast cancer oncogene, functions as a transforming kinase by activating NF-κB. IKKε is often elevated in breast cancers in the absence of any gene amplification. Because Akt-mediated transformation was shown to require IKKε, we examined if Akt regulates IKKε level in breast cancer cells. Knockdown of Akt2, but not other Akt isoforms, decreased the basal and TNF-induced IKKε protein and mRNA level, and overexpression of Akt2 in MDA-MB-231 cells increased IKKε level. The decrease in IKKε level by Akt2 knockdown was not only restricted to MDA-MB-231 cells but was also observed in several other breast cancer cells, including HCC1937 and MCF-10CA1a cells. Knockdown of p65/RelA subunit of NF-κB decreased IKKε level and attenuated the increase in IKKε caused by Akt2 overexpression, suggesting that Akt2-mediated induction of IKKε involves NF-κB activation. Silencing of IKKε also decreased long-term clonogenic survival of Akt2-overexpressing MDA-MB-231 cells. Taken together, these results demonstrate for the first time that IKKε functions downstream of Akt2 to promote breast cancer cell survival.

Abstract. Protein kinase C epsilon (PKCÂ) is a transforming oncogene and an important anti-apoptotic protein. We previously demonstrated that overexpression of PKCÂ in MCF-7 breast cancer cells caused an increase in anti-apoptotic Bcl-2 and a decrease in pro-apoptotic Bid, attenuating tumor necrosis factor-· (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. The objective of our present study was to determine the mode of induction of Bcl-2 by PKCÂ in breast cancer cells. siRNA silencing of either PKCÂ or Akt in MCF-7 cells, which overexpress Akt, decreased Bcl-2 protein and mRNA levels. However, knockdown of PKCÂ, but not Akt, led to the decrease in Bcl-2 at both protein and mRNA levels in MDA-MB-231 breast cancer cells, which overexpress PKCÂ but contain little constitutivelyactive Akt. Knockdown of PKCÂ decreased phosphorylation of cAMP response element-binding protein (CREB) at Ser133 in MDA-MB-231 cells, and depletion of CREB by siRNA decreased Bcl-2 at both the protein and mRNA levels. In addition, knockdown of CREB sensitized MDA-MB-231 cells to TRAIL-mediated cell death. These results suggest that PKCÂ regulates Bcl-2 induction through activation of the transcription factor CREB.