Targeting ZAKα Interactions and Ribosomes with Novel peptides: The role of ZAKα in Mitochondrial Function and Cancer Cell Proliferation

Abstract

Phage display was used to identify high-affinity and high-specificity peptides that might inhibit ZAKα, a kinase implicated in cellular proliferation, differentiation, and stress response and implicated in both malignant tumor growth and metastasis as well as the pathogenesis of cardiac hypertrophy and fibrotic heart disease. Two peptides were found to specifically bind to ZAKα, PhD30 and PhD35. Their introduction into cancer cells led to the dissociation of ZAKα from RPS20 and the ubiquitination of RPS20 protein resulting in a reduction of essential mitochondria proteins and mitochondria activity impeding the translation of mitochondrial-associated eukaryotic ribosomes, a process we believe to be crucial for tumor growth. This mechanism of action suggests that the primary effect of PhD30 and PhD35 is to lower mitochondrial activity by causing a shortage of essential proteins in mitochondria without changing the number of apoptotic and necrotic cancer cells. Thus, these findings may prove pivotal to the development of a novel approach utilizing these peptides to inhibit cancer cell growth by targeting mitochondrial function, rather than the conventional method of inducing apoptosis.