Loss of p53 expression in cancer cells alters cell cycle response after inhibition of exportin-1 but does not prevent cell death

Abstract

The tumor suppressor protein p53 is central to the cellular stress response and may be a predictive biomarker for cancer treatments. Upon stress, wildtype p53 accumulates in the nucleus where it enforces cellular responses, including cell cycle arrest and cell death. p53 is so dominant in its effects, that p53 enforcement - or - restoration therapy is being studied for anti-cancer therapy. Two mechanistically distinct small molecules that act via p53 are the selective inhibitor of nuclear export, selinexor, and MDM2 inhibitor, nutlin-3a. Here, individual cells are studied to define cell cycle response signatures, which captures the variability of responses and includes the impact of loss of p53 expression on cell fates. The individual responses are then used to build the population level response. Matched cell lines with and without p53 expression indicate that while loss-of-function results in altered cell cycle signatures to selinexor treatment, it does not diminish overall cell loss. On the contrary, response to single-agent nutlin-3a shows a strong p53-dependence. Upon treatment with both selinexor and nutlin-3a there are combination effects in at least some cell lines - even when p53 is absent. Collectively, the findings indicate that p53 does act downstream of selinexor and nutlin-3a, and that p53 expression is dispensable for selinexor to cause cell death, but nutlin-3a response is more p53-dependent. Thus, TP53 disruption and lack of expression may not predict poor cell response to selinexor, and selinexor's mechanism of action potentially provides for strong efficacy regardless of p53 function.

AML-Related NPM Mutations Drive p53 Delocalization into the Cytoplasm with Possible Impact on p53-Dependent Stress Response

“…Therefore, it raises a question whether the NPM mutation could alter NPM phosphorylation with expected effects on p53 activation. We conclude that induction of p53 might explain the positive therapeutic effect of Selinexor in the treatment of AML with NPMmut, possibly in combination with other p53-inducing agents, such as mdm2/p53 inhibitors, e.g., nutlin-3a [43].…”

“…Targeting the cytoplasmic p53 and restoration of its nuclear localization could be therefore a promising alternative for the therapy of the AML with NPMmut. An inhibition of XPO1 by Selinexor [43,69] or any other clinically efficient inhibitor, e.g., verdinexor [70], seems to be an auspicious choice [41].…”

“…The proteasome-mediated p53 degradation can also be affected by the p53 translocation [42]. Therapeutic restoration of the p53 functionality therefore seems to be a promising anticancer approach [43]. As NPM and p53 mutations are mutually exclusive in AML, the return of wild type p53 to the nucleus could re-establish its tumor suppressor and cell cycle inhibitor function.…”

XPO1/CRM1 is a promising prognostic indicator for neuroblastoma and represented a therapeutic target by selective inhibitor verdinexor

“…In this case, the anti-tumor effects of XPO1 mainly depended on the function of P53, and P53 mutation would lead to strong drug resistance. However, for human fibrosarcoma cells HT-1080 and breast cancer cells MCF7, loss of p53 function altered cell cycle arrest after inhibition of XPO1 but didn’t weaken the anti-tumor effects [ 42 ]. This might be XPO1 strengthened the regulation of other anti-cancer targets or pathways in the absence of P53 function.…”

Exploring the Antioxidant Effects and Periodic Regulation of Cancer Cells by Polyphenols Produced by the Fermentation of Grape Skin by Lactobacillus plantarum KFY02

“…The p53 gene is closely related to the occurrence, development, and clinical treatment of tumors [35]. It is involved in the regulation of cell cycle, DNA repair, cell differentiation, apoptosis, and other anticancer biological functions [36,37,38]. The expression product of the p21 gene is the most widely known kinase inhibitor.…”