Protein Kinase C ß: a New Target Therapy to Prevent the Long-Term Atypical Antipsychotic-Induced Weight Gain.

Antipsychotic drugs are currently used in clinical practice for a variety of mental disorders. Among them, clozapine is the most effective medication for treatment-resistant schizophrenia and is most helpful in controlling aggression and the suicidal behavior in schizophrenia and schizoaffective disorder. Although clozapine is associated with a low likelihood of extrapyramidal symptoms and other neurological side effects, it is well known for the weight gain and metabolic side effects, which expose the patient to a greater risk of cardiovascular disorders and premature death, as well as psychosocial issues, leading to non-adherence to therapy. The mechanisms underlying these iatrogenic metabolic disorders are still controversial. We have therefore investigated the in vivo effects of the selective PKCß inhibitor, ruboxistaurin (LY-333531), in a preclinical model of long-term clozapine-induced weight gain. Cell biology, biochemistry, and behavioral tests have been performed in wild-type and PKCß knockout mice to investigate the contribution of endogenous PKCß and its pharmacological inhibition to the psychomotor effects of clozapine. Finally, we also shed light on a novel aspect of the mechanism underlying the clozapine-induced weight gain, demonstrating that the clozapine-dependent PKCß activation promotes the inhibition of the lipid droplet-selective autophagy process. This paves the way to new therapeutic approaches to this serious complication of clozapine therapy.

Chemoresistance and Cancer-Related Inflammation: Two Hallmarks of Cancer Connected by an Atypical Link, PKCζ.

Atypical protein kinase C isoforms are serine threonine kinases involved in various pathological conditions. In recent years, the PKCζ isoform has emerged as an important regulator of multiple cellular processes operating in cancer. In this review, we will focus on the PKCζ isoform as an oxidative-sensing kinase involved in cancer-related inflammation and chemoresistance. We will discuss its nuclear localization and its possible pivotal role in connecting inflammation with drug resistance.