دانلود رایگان مقاله انگلیسی کنترل پسارونویسی پاسخ های استرس در سرطان - الزویر 2018

The processes by which the canonical protein synthesis machinery is modified by environmental stresses to allow healthy cells to respond to external conditions to maintain homeostasis, are frequently hijacked by tumour cells to enhance their survival. Two major stress response pathways that play a major role in this regard are the unfolded protein response (UPR) and the DNA damage response (DDR). Recent data have shown that key proteins which coordinate post-transcriptional control, and which are regulated by signalling through the UPR and DDR, are upregulated in cancers and that targeting these proteins/ pathways will provide new therapeutic avenues for cancer treatments.

Conclusions and future perspectives

Cancer cells take advantage of evolutionary conserved stress response pathways and post-transcriptional regulatory mechanisms to promote tumourigenesis and therapeutic resistance. Subsequently, these pathways have emerged as important therapeutic targets.

It has been proposed that targeting the UPR may be a promising method to treat cancers, however as discussed above, the effects of this stress response pathway on tumour development and maintenance are more complicated than originally anticipated, and dependent on both tumour stage and grade [12]. Therefore, extreme caution would be necessary when considering such targeting to ensure that pro-survival and pro-apoptotic roles of this pathway in individual tumour cells were fully explored [20,46]. Moreover, the phosphorylation of eIF2a generally promotes cell survival in response to stress [47], therefore, therapeutic targeting of eIF2a phosphorylation in conjunction with standard chemotherapy offers a unique opportunity to target tumours [35

]. However, treatment of cancer cell lines with an inhibitor of eIF2a phosphatases, subsequently enhancing eIF2a phosphorylation, sensitised cells to the chemotherapeutic doxorubicin [48], suggesting that these mechanisms, as with those observed in the UPR, could be tumour, cell line or therapeutic agent specific. Furthermore, the application of mTOR inhibitors individually, or in combination with alternative therapies, remains a crucial tool in the treatment of cancer, but as with platinum-based chemotherapy [30

], their effectiveness may be tumour type specific.