Carfilzomib triggers cardiotoxicity by suppressing SENP1-mediated deSUMOylation of DDX17

Abstract

Carfilzomib (Cfz) is a second-generation proteasome inhibitor approved for the treatment of relapsed/refractory multiple myeloma (RRMM). Previous studies have shown that Cfz is associated with a higher incidence of severe adverse cardiac effects than bortezomib (Btz); however, the underlying mechanisms remain to be elucidated. The aim of this study is to identify key regulators of cardiotoxicity induced by Cfz and to investigate the mechanisms by which these factors exert their effects. We establish a mouse model of cardiac toxicity induced by Cfz and confirm the phenotype through cardiac functional analysis, morphology assessment, myocardial fibrosis, and apoptosis analysis. We subsequently perform RNA sequencing to identify differentially expressed genes (DEGs) and further validate their functions and mechanisms. We find that Cfz induces myocardial hypertrophy and myocardial injury, along with the suppression of SENP1 expression in mouse heart tissues and in vitro cultured neonatal rat cardiomyocytes. Suppression of SENP1 exacerbates Cfz-induced injury and remodeling in cardiomyocytes by directly binding to and deconjugating the SUMO1-mediated SUMOylation of the RNA helicase DDX17. This process leads to a reduction in K-48 ubiquitin-linked polyubiquitination and degradation of DDX17, resulting in increased expressions of anti-apoptotic genes and maintenance of mitochondrial homeostasis. Therefore, the overexpression of SENP1 using AAV vectors alleviates Cfz-induced cardiotoxicity in mice. In summary, our findings reveal a previously unknown role of the SENP1-DDX17 axis in protecting against cardiotoxicity induced by Cfz, providing a potential foundation for developing therapeutic strategies to mitigate cardiac side effects in the clinical management of MM patients.

1. Introduction

Multiple myeloma (MM) is the second most common hematological malignancy and is characterized by abnormal proliferation of plasma cells in the bone marrow niche and the presence of a monoclonal immunoglobulin protein [1]. Bortezomib (Btz) is the first proteasome inhibitor (PI) approved for the treatment of newly diagnosed MM (NDMM), and carfilzomib (Cfz) is the first second-generation PI approved for the management of refractory or relapsed MM (RRMM), both of which have substantially improved the clinical outcome of MM patients [2]. However, PIs inhibit proteasome activity in cardiomyocytes and are associated with a significant incidence of cardiotoxicity, including hypertension (HTN), ischemic heart disease (IHD), heart failure (HF), and ventricular arrhythmia (VA) [3]. Among the PIs approved for clinical application, carfilzomib is the most strongly associated with cardiotoxicity [4]. PIs trigger the transcriptional activation of signaling pathways, such as NF-κB and autophagy, and those involved in regulating nitric oxide homeostasis may contribute to these cardiotoxic effects [5]. The underlying molecular mechanisms of therapy-associated cardiotoxic effects have been increasingly elucidated, but detailed mechanistic illustrations are still lacking.

Protein posttranslational modifications (PTMs) are essential for regulating various physiological and pathological processes within cells [6]. SUMOylation, a reversible PTM, contributes to the pathogenesis of cardiovascular diseases [7]. The covalent binding of SUMO proteins to their target proteins is a dynamic and reversible process regulated by the coordinated activities of SUMO-conjugating and deconjugating enzymes. In mammalian cells, the most prevalent group of deconjugating enzymes is the sentrin-specific proteases (SENPs), which consists of six members: SENP1, SENP2, SENP3, SENP5, SENP6, and SENP7 [8]. Among these SENPs, SENP1 exerts a protective effect on cardiac dysfunction after myocardial injury by facilitating the proteasomal degradation of HSP90ab1 [9]. However, whether SENP1 is critical for the development of cancer and therapy-related cardiotoxicity, particularly in multiple myeloma and Cfz-based regimens, remains unknown.