Research ArticleCancer

Tissue-specific regulation of p53 by PKM2 is redox dependent and provides a therapeutic target for anthracycline-induced cardiotoxicity

See allHide authors and affiliations

Science Translational Medicine  06 Feb 2019:
Vol. 11, Issue 478, eaau8866
DOI: 10.1126/scitranslmed.aau8866

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Killing two birds with one protein

Anthracyclines, a class of common chemotherapy drugs, frequently cause cardiac damage. This cardiotoxicity is associated with activation of p53, a protein that stimulates apoptosis in tumors and in other organs such as the heart, causing nonspecific tissue injury. Saleme et al. found that pyruvate kinase muscle 2 (PKM2) directly interacts with p53. The tetrameric form of PKM2 is preferentially oxidized in the heart, where it suppresses apoptosis. Conversely, the same tetramer enhances the activity of p53 in low oxidation environments such as tumors. The authors identified a compound that stabilizes tetrameric PKM2, protecting cardiomyocytes while facilitating cancer cell killing by anthracyclines.

Abstract

Chemotherapy-induced cardiotoxicity (CIC) is a common clinical problem that compromises effective anticancer therapies. Many chemotherapeutics (including anthracyclines, such as doxorubicin) induce the proapoptotic transcription factor p53 in the tumor and nonspecifically in the heart, promoting heart failure. Although inhibition of p53 shows benefit in preclinical heart failure models, it would not be an attractive adjuvant therapy for CIC, because it would prevent tumor regression. A p53-targeting therapy that would decrease chemotherapy-induced apoptosis in the myocardium and, at the same time, enhance apoptosis in the tumor would be ideal. Here, we propose that differences in oxygen tension between the myocardium and the tumor could provide a platform for redox-dependent tissue-specific therapies. We show by coimmunoprecipitation and mass spectrometry that the redox-regulated pyruvate kinase muscle 2 (PKM2) directly binds with p53 and that the redox status of cysteine-423 of tetrameric (but not monomeric) PKM2 is critical for the differential regulation of p53 transcriptional activity. Tetrameric PKM2 suppresses p53 transcriptional activity and apoptosis in a high oxidation state but enhances them in a low oxidation one. We show that the oxidation state (along with cysteine-423 oxidation) is higher in the heart compared to the tumor of the same animal. Treatment with TEPP-46 (a compound that stabilizes tetrameric PKM2) suppressed doxorubicin-induced cardiomyocyte apoptosis, preventing cardiac dysfunction, but enhanced cancer cell apoptosis and tumor regression in the same animals in lung cancer models. Thus, our work suggests that redox-dependent differences in common proteins expressed in the myocardium and tumor can be exploited therapeutically for tissue selectivity in CIC.

View Full Text