Cisplatin-induced apoptosis and development of resistance are transcriptionally distinct processes

Cisplatin is a cornerstone treatment for numerous malignancies, including lung cancer. Despite the extensive research on the mechanisms by which this platinum compound exerts its potent anticancer effects, the predominant mode of action is unclear. It was originally thought that cisplatin inflicts mainly DNA damage, leading to cancer cell death.¹ Additional research revealed that cisplatin can also kill cancer cells that lack their nucleus, indicating that the targeting of cytoplasmic molecules is equally effective.^2,3 Genetic or epigenetic disruption of any of these pathways or cellular adaptation mechanisms to this toxic agent is likely to lead to the development of resistance. In fact, resistance to cisplatin is the most frequent clinical outcome despite the initial beneficial anticancer effects induced by this drug. In a recent issue of Cell Cycle, Galluzzi et al., utilized multi-faceted approaches in an attempt to answer some of the aforementioned questions.⁴ One of these approaches involved a comprehensive analysis of the transcriptional signatures elicited by cisplatin. The findings of this array provide further support to the notion that cisplatin-induced apoptosis is largely transcription-independent. However, the adaptation of the cancer cells to the cytotoxic insults inflicted by cisplatin and the ensuing development of resistance may depend on the expression of key proteins. The authors found that two genes that may confer resistance were found to be transcriptionally upregulated by cisplatin. The transcription of PDXK, an enzyme involved in vitamin B6 metabolism and required for optimal cisplatin cytotoxic responses, is downregulated in A549 cells.⁵ Another gene that is transcriptionally downregulated by cisplatin is DHRSX, an oxidoreductase that may mediate the lethal effects of cisplatin by the generation of cytotoxic reactive oxygen species. The most significantly upregulated gene is RRAD, a Ras-related GTPase that is upregulated. The functional significance of this induction in RRAD gene expression is not clear. RRAD has been shown to promote apoptosis by activating the p38 MAPK and by decreasing the expression of Bcl-xL.⁶ Importantly, RRAD gene expression is epigenetically downregulated in prostate cancer clinical samples.⁷ The mechanisms behind the transcriptional regulation of these proteins are not known and deserve further investigation. Overall, this study provides novel insights on the cell death signaling cascades induced by cisplatin as well as on mechanisms of resistance, exploitation of which may improve the efficacy of this anticancer drug in the clinic.

Galluzzi L, Vitale I, Senovilla L, Eisenberg T, Carmona-Gutierrez D, Vacchelli E, Robert T, Ripoche H, Jägemann N, Paccard C, Servant N, Hupé P, Lazar V, Dessen P, Barillot E, Zischka H, Madeo F, Kroemer G. Independent transcriptional reprogramming and apoptosis induction by cisplatin. Cell Cycle. 2012;11:3472–80. doi: 10.4161/cc.21789.