Targeting c-Myc Unbalances UPR towards Cell Death and Impairs DDR in Lymphoma and Multiple Myeloma Cells

Abstract

Multiple myeloma (MM) and primary effusion lymphoma (PEL) are aggressive hematological cancers, for which the search for new and more effective therapies is needed. Both cancers overexpress c-Myc and are highly dependent on this proto-oncogene for their survival. Although c-Myc inhibition has been shown to reduce PEL and MM survival, the underlying mechanisms leading to such an effect are not completely clarified. In this study, by pharmacologic inhibition and silencing, we show that c-Myc stands at the cross-road between UPR and DDR. Indeed, it plays a key role in maintaining the pro-survival function of UPR, through the IRE1α/XBP1 axis, and sustains the expression level of DDR molecules such as RAD51 and BRCA1 in MM and PEL cells. Moreover, we found that c-Myc establishes an interplay with the IRE1α/XBP1 axis whose inhibition downregulated c-Myc, skewed UPR towards cell death and enhanced DNA damage. In conclusion, this study unveils new insights into the molecular mechanisms leading to the cytotoxic effects of c-Myc inhibition and reinforces the idea that its targeting may be a promising therapeutic approach against MM and PEL that, although different cancers, share some similarities, including c-Myc overexpression, constitutive ER stress and poor response to current chemotherapies.

Concomitant Inhibition of IRE1α/XBP1 Axis of UPR and PARP: A Promising Therapeutic Approach against c-Myc and Gammaherpesvirus-Driven B-Cell Lymphomas

“…We then extended this study to BCBL1 PEL cells, a B-cell lymphoma in which the pro-survival role of XBP1s [ 25 ] and the cross-talk of this molecule with c-Myc has been previously shown [ 10 ]. Interestingly, 4μ8C, which efficiently reduced XBP1s expression ( Figure 5 B), increased the cytotoxicity of AZD2461 also in these cells compared to the single treatments ( Figure 5 A).…”

“…However, as for other cancers, lymphoma cells overexpressing c-Myc are characterized by a high level of constitutive stress, which renders them highly dependent on the activation of UPR sensors such as IRE1α [ 13 ]. The cytotoxic effect of IRE1α/XBP1 inhibition by 4μ8C correlated with the downregulation of c-Myc in BL cells, given that the latter may engage a positive feedback loop with XBP1s to sustain the survival of cancers [ 6 , 10 ]. Targeting UPR has also been reported to be effective in reducing cell survival of mutp53-carrying cancers through the upregulation of the pro-apoptotic UPR molecule CHOP [ 31 ], even if the presence of mutp53 may render cancer cells more resistant to such treatment [ 32 ].…”

“…In this regard, we have recently shown that targeting c-Myc reduces the constitutive activation of XBP1s, unbalancing UPR towards cell death. Moreover, c-Myc inhibition impaired DNA damage response (DDR) both in multiple myeloma (MM) and in PEL cells [ 10 ]. Indeed, XBP1s have the capacity to upregulate the expression of several molecules involved in DDR, either belonging to Homologous Repair (HR) and non-homologous end joining (NHEJ) repair.…”

Interconnected Adaptive Responses: A Way Out for Cancer Cells to Avoid Cellular Demise

“…CMA is a process that involves HSPc70, and this highlights once again the key role of HSPs in the intricate network of the adaptive processes that sustain cancer survival, even if CMA, when leading to the degradation of oncogenes, can prevent carcinogenesis rather than promoting it. In particular, as CMA contributes to the regulation of c-myc expression level, it not only influences DDR, sustaining the expression of RAD51 and BRCA-1 but also affects UPR, promoting its pro-survival functions [ 74 , 75 ]. Another important aspect to be considered is that besides UPR, DDR has been reported to influence the release of inflammatory cytokines [ 74 , 76 ], thus, contributing to shaping the tumor microenvironment.…”

c-Myc Sustains Pancreatic Cancer Cell Survival and mutp53 Stability through the Mevalonate Pathway

“…Indeed, among the numerous consequences of HSP targeting, the reduction in mutp53 is particularly important as it may prevent the oncogenic effects induced by this protein when it undergoes some types of mutations [ 8 , 22 , 23 , 24 , 25 ]. Last but not least, c-Myc is strongly involved in the regulation of DNA damage repair (DDR) both in wt and mutp53 carrying cancer cells, which may have important implication in cancer survival and response to therapies [ 26 ], and interestingly, the mevalonate pathway has been also shown to regulate such a response [ 27 ]. Therefore, the interconnection between c-Myc, the mevalonate pathway and mutp53 was investigated in this study by inhibiting c-Myc in pancreatic cancer cells.…”