Harnessing RKIP to Combat Heart Disease and Cancer

SIMPLE SUMMARY: Two major causes of mortality in the world today are cancer and heart disease. Although these are distinct diseases, their pathomechanisms rely partially on common signaling pathways driven by kinases such as β-adrenoceptor/protein kinase A (PKA) and the mitogen-activated protein (MAP) kinase network. Furthermore, activation of these kinases can lead to both positive and deleterious effects on disease progression. Thus, the goal of therapeutic strategies should be to promote the normalization of these signaling pathways under pathological conditions. Raf kinase inhibitory protein (RKIP) represents a physiological mechanism for achieving this outcome. As a regulator of the cellular kinome, RKIP acts in its unphosphorylated form as a suppressor of metastatic cancer progression by decreasing MAPK signaling. Conversely, in its phosphorylated form, RKIP protects against heart failure by upregulating β-adrenoceptor/PKA signaling. Here we discuss how leveraging RKIP action by using selective targeting strategies has the potential for the cardio-safe treatment of cancer. ABSTRACT: Cancer and heart disease are leading causes of morbidity and mortality worldwide. These diseases have common risk factors, common molecular signaling pathways that are central to their pathogenesis, and even some disease phenotypes that are interdependent. Thus, a detailed understanding of common regulators is critical for the development of new and synergistic therapeutic strategies. The Raf kinase inhibitory protein (RKIP) is a regulator of the cellular kinome that functions to maintain cellular robustness and prevent the progression of diseases including heart disease and cancer. Two of the key signaling pathways controlled by RKIP are the β-adrenergic receptor (βAR) signaling to protein kinase A (PKA), particularly in the heart, and the MAP kinase cascade Raf/MEK/ERK1/2 that regulates multiple diseases. The goal of this review is to discuss how we can leverage RKIP to suppress cancer without incurring deleterious effects on the heart. Specifically, we discuss: (1) How RKIP functions to either suppress or activate βAR (PKA) and ERK1/2 signaling; (2) How we can prevent cancer-promoting kinase signaling while at the same time avoiding cardiotoxicity.