LAUSR

Letter by Cristóbal et al Regarding Article, “Protein Phosphatase 2A Regulates Cardiac Na+ Channels” To the Editor: We have read with great interest the recently published work by El Refaey et al, which demonstrates that PP2A (protein phosphatase 2A) plays a key role regulating cardiac Na channels and identifies the PP2A regulatory subunit B56α as a novel potential molecular target to impair arrhythmogenic activity of cardiac sodium channel Na V 1.5 late current (I Na,L ). The authors showed that B56α deficient mice displayed altered cardiomyocyte excitability as well as decreased sensibility to adrenergic stimulation and observed a marked reduction of I Na,L in B56α knockout mouse cardiomyocytes compared to wildtype myocytes. Of note, CaMKII (Ca/calmodulin-dependent kinase II) associates with ankyrin-G which results in the formation of a CaMKII regulatory complex that interacts with Na V 1.5. Then, CaMKII phosphorylates Na V 1.5, which is critical for I Na and I Na,L regulation. El Refaey et al identified in their work that PP2A/B56α colocalizes and associates with the CaMKII complex. Interestingly, PP2A/B56α plays a key role positively regulating CaMKII-dependent Na V 1.5 phosphorylation, because myocytes lacking B56α showed reduced arrhythmogenic I Na,L . These interesting results highlight that PP2A/B56α represents a novel target for the treatment of arrhythmia. However, there are additional considerations that should be taken into account. PP2A is a tumor suppressor frequently inactivated in human cancer and deregulation of the PP2A endogenous inhibitor SET (SET nuclear proto-oncogene) represents a key molecular mechanism to inhibit this phosphatase in the tumor cell. In fact, SET has been reported to bind and specifically inhibit the activity of PP2A/B56 complexes. Thus, several strategies based on the use of PP2A activating drugs, such as FTY720 or SET antagonists, have been progressively emerging in the last years as novel promising therapeutic approaches for many cancers. In fact, it has been reported that the use of PP2A activators sensitizes tumor cells to both standard chemotherapeutic compounds and hormone therapies, and their potential combination has been largely proposed. However, the development of cardiomyopathies, including arrhythmia, is a relevant adverse effect of antineoplastic chemotherapy, and sex hormones alter ventricular repolarization enhancing the incidence of cardiac arrhythmias in patients receiving hormone-therapy in high prevalent tumors, such as breast or prostate cancers. In conclusion, cancer therapy-induced cardiomyopathy as a current clinical complication together with the emerging role of PP2A regulating the molecular mechanisms of proarrhythmic represent relevant issues to be considered in the field of cardio-oncology. Thus, it remains necessary to evaluate the potential risk of developing cardiomyopathies such as cardiac arrhythmia by the future inclusion of PP2A activating drugs combined with standard therapies in anticancer protocols.