Cellular Responses to Cisplatin-Induced DNA Damage
Figure 1
Cellular responses to cisplatin-induced DNA damage. Entry of cisplatin into cells by passive diffusion (indicated by dotted arrows), carrier-mediated transport, employing copper transporter-1 (CTR1). Efflux of cisplatin from the cells by the ATP-dependent transporters, ATP7A and ATP7B. Cisplatin binds to cellular thiols, such as glutathione and metallothionein. The glutathione-cisplatin conjugates are further transported from the cells by the ATP-dependent, GS-X pumps. Once cisplatin interacts with DNA, it stalls cell proliferation by inhibiting DNA synthesis, followed by activation of DNA damage response. Cisplatin-DNA adducts is primarily repaired via the nucleotide excision repair (NER) system and also induces cell-cycle arrest. The DNA damage response is transduced mainly via p53 and c-Abl. Cisplatin-induced DNA damage activates p53, leading to the induction of p21, GADD45, proapoptotic PUMA, caspase-6, -7, and microRNAs such as miR-34a. p53 also promotes cisplatin-induced apoptosis by binding and inhibiting the antiapoptotic Bcl-xL and also by degradation of FLIP. Cisplatin-DNA adducts activates the mismatch repair system which further activates c-Abl, leading to the activation of JNK and p38 MAPK and stabilization of p73 resulting in apoptosis. Kinases such as PKC, ERK, and Akt are also involved in the regulation of cisplatin-induced cell death. miR-214 promotes cisplatin resistance by downregulating PTEN and activating Akt.