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

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.

Propofol Protects Myocardium From Ischemia/Reperfusion Injury by Inhibiting Ferroptosis Through the AKT/p53 Signaling Pathway

“…In the present study, we found that propofol improved the antioxidant capacity of cardiomyocytes by improving the levels of FTH1, XCT, or GPX4 and reducing iron levels. Another study has shown that p53 inhibits cysteine absorption by downregulating XCT expression ( Magri et al, 2021 ), resulting in the inhibition of cystine-dependent glutathione oxidase activity and increased cell lipid ROS, leading to ferroptosis ( Jiang et al, 2015 ). Our results showing propofol downregulation of p53 and reduction of cardiomyocyte dysfunction are consistent with the previous study ( Lai et al, 2011 ).…”

Transcriptional Regulation of Amino Acid Transport in Glioblastoma Multiforme

“…The SXC inhibitor also synergizes with PRIMA-1 in vitro to lower GSH levels in non-small lung cancer H2199 cells with mutant p53 [ 38 ]. These studies, and ours, suggest that PRIMA-1 Met may be an attractive candidate for targeting the intracellular effects of xCT by impairing cancer stem cell antioxidant defense mechanisms [ 43 ]. However, although we did use the more lipophilic, methylated version of this small molecule, our intracranial study ( Figure S2 ), in combination with previous work [ 28 ], suggests that PRIMA-1 Met may have poor blood–brain barrier permeability.…”

Cancer Immunology: From Molecular Mechanisms to Therapeutic Opportunities

“…On the other hand, mutant p53 protein is endowed with the capability to induce a transcriptional downregulation of xCT with concomitant induction of ferroptosis. In this review the authors described the direct and indirect pathways between p53 and xCT, to be employed for new combination cancer therapies based on the use of mutant forms of p53 together with xCT [25].…”