Review Article

Cellular Responses to Cisplatin-Induced DNA Damage

Figure 1

Cellular responses to cisplatin-induced DNA damage. [ 1 ] Entry of cisplatin into cells by passive diffusion (indicated by dotted arrows), carrier-mediated transport, employing copper transporter-1 (CTR1). [ 2 ] Efflux of cisplatin from the cells by the ATP-dependent transporters, ATP7A and ATP7B. [ 3 ] 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. [ 4 ] Once cisplatin interacts with DNA, it stalls cell proliferation by inhibiting DNA synthesis, followed by activation of DNA damage response. [ 5 ] 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 𝛼 , 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. [ 6 ] Kinases such as PKC, ERK, and Akt are also involved in the regulation of cisplatin-induced cell death. [ 7 ] miR-214 promotes cisplatin resistance by downregulating PTEN and activating Akt.
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