Tumor-Associated Antigen xCT and Mutant-p53 as Molecular Targets for New Combinatorial Antitumor Strategies.

Jolanda Magri,Laura Conti,Giuseppina Barutello,Chiara Cossu,Enzo Calautti,Federica Cavallo,Alessandro Gasparetto,Roberto Ruiu

doi:10.3390/cells10010108

Abstract

The cystine/glutamate antiporter xCT is a tumor-associated antigen that has been newly identified in many cancer types. By participating in glutathione biosynthesis, xCT protects cancer cells from oxidative stress conditions and ferroptosis, and contributes to metabolic reprogramming, thus promoting tumor progression and chemoresistance. Moreover, xCT is overexpressed in cancer stem cells. These features render xCT a promising target for cancer therapy, as has been widely reported in the literature and in our work on its immunotargeting. Interestingly, studies on the TP53 gene have revealed that both wild-type and mutant p53 induce the post-transcriptional down modulation of xCT, contributing to ferroptosis. Moreover, APR-246, a small molecule drug that can restore wild-type p53 function in cancer cells, has been described as an indirect modulator of xCT expression in tumors with mutant p53 accumulation, and is thus a promising drug to use in combination with xCT inhibition. This review summarizes the current knowledge of xCT and its regulation by p53, with a focus on the crosstalk of these two molecules in ferroptosis, and also considers some possible combinatorial strategies that can make use of APR-246 treatment in combination with anti-xCT immunotargeting.

Highlights

Cancer is one of the leading causes of death in the world
The increased therapeutic efficacy of the combination of APR-246 and xCT inhibitors is unlikely to be the result of the restoration of wt-p53 functions with respect to SLC7A11 gene expression, since wt-p53 should lead to its transcriptional repression, albeit through a distinct molecular mechanism, but rather it appears to depend on APR-246 oxidative stress induction (Figure 3)
Evidence from research and clinics has clarified that effective cancer treatment requires the simultaneous targeting or modulation of several pathways and biological functions that play key roles in cancer cell survival, such as oncogenic pathways, cell metabolism and redox balance

Summary

Introduction

Cancer is one of the leading causes of death in the world. cancer therapy has improved in the past few decades, therapy failure is still common, resulting in poor patient outcomes. XCT amino acid transport, and not its antioxidant function, seems to be responsible for cell death upon glucose starvation, since xCT upregulation occurs independently of ROS generation under these conditions [22] It is still unclear whether cystine uptake or glutamate export is the main cause of glucose addiction in cancer cells with elevated xCT expression. The altered metabolic state caused by xCT expression has consequences on mitochondrial functions, with mitochondrial genes being upregulated because of the increased OXPHOS [20] Overall, these studies provide evidence that supports the key role played by xCT in both redox homeostasis and nutrient dependency in cancer cells, as discussed in detail by Koppula et al [27]. P53 is one of the most interesting cellular targets for limiting tumor growth while translationally improving the duration and quality of a patient’s life

Principles of p53 Targeted Therapy

PRIMA-1 and Its Analogues

Findings

Conclusions