PKCα

A ground-breaking study has revealed crucial insights into the role of the histone methyltransferase NSD2 and its epigenetic target PKC-alpha in causing t(4;14) translocated multiple myeloma (MM), a high-risk subtype of blood cancer, to be more aggressive and resistant to treatment. A ground-breaking study by researchers from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS) has revealed crucial insights into the role of the histone methyltransferase NSD2 and its epigenetic target PKCα in causing t(4;14) translocated multiple myeloma (MM), a high-risk subtype of blood cancer, to be more aggressive and resistant to treatment. The study was led by Professor Wee Joo Chng, Senior Principal Investigator at CSI Singapore, and Dr Phyllis Chong Shu Yun, Senior Research Fellow at CSI Singapore. The research team discovered that NSD2 triggers elevated glycolysis through the activation of PKCα, leading to the production of excessive lactate that fuels malignancy and undermines response to immunomodulatory drugs. The findings present potential targets to improve the treatment of myeloma. Targets for therapeutic intervention Myeloma is the second most common blood cancer, and t(4;14) myeloma comprises 15 to 20 per cent of MM cases. Compared to other types of myeloma, patients with t(4;14) myeloma have a poorer prognosis with shorter overall survival. Unfortunately, the key deregulated gene in t(4;14) myeloma is not targetable with drugs. "Our study aims to overcome the limitations of targeting the key deregulated gene in t(4;14) myeloma. It sheds light on the metabolic reprogramming of MM in response to the oxygen- and nutrient-deprived bone marrow microenvironment. By exploring the epigenome and metabolome of NSD2, we sought alternative vulnerabilities that could revolutionise treatment strategies," said Prof Chng, lead author of the study. The unique connection between NSD2 and cellular metabolism, mediated by histone methylation, offers new horizons in the battle against high-risk MM subtypes. The study's impact is multifaceted, potentially influencing the development of novel medicines and non-invasive diagnostic tests. For patients with t(4;14) myeloma, targeted metabolic interventions could bring promising therapeutic options, whether through dietary modifications or tailored pharmacological approaches. Furthermore, the discovery that lactate levels could serve as predictive biomarkers for drug response highlights the transformative potential of metabolite signatures in personalised medicine. Striving towards tailored interventions and personalised care This study, which was published in Cancer Research, American Association for Cancer Researchon 18 July 2023, marks a significant stride in unravelling the complexities of MM and holds promise to improving treatment outcomes for patients with high-risk subtypes. Looking ahead, Prof Chng and his team plan to leverage the knowledge gained from this study to design therapeutic intervention for t(4;14) myeloma. The success of their metabolic characterisation of t(4;14) myeloma also paves the way for the team to extend their metabolomic framework to pro genetically high-risk MM subtypes such as t(14;16) or with 1q21 amplifications, presenting a path towards tailored interventions and personalised care.

Researchers identify the PKC-alpha enzyme as a promising therapeutic target in Alzheimer's disease; a mutation that increases its activity led to biochemical, cellular and cognitive impairments in mice. In a recent search for gene variants associated with Alzheimer's disease (AD), several affected families showed a mutation in an enzyme called protein kinase C-alpha (PKCα). Family members with this mutation had AD; those without the mutation did not. The M489V mutation has since been shown to increase the activity of PKCα by a modest 30 percent, so if and how it contributes to the neuropathology of AD has remained unclear. In a new study, researchers at University of California San Diego School of Medicine found that the subtle increase in PKCα was sufficient to produce biochemical, cellular and cognitive impairments in mice, similar to those observed in human AD. The findings, published online on November 23, 2022 in Nature Communications, position PKCα as a promising therapeutic target for the disease. PKCα regulates the function of many other proteins, particularly in the brain. The enzyme facilitates chemical reactions that add phosphate groups to other proteins, shaping their activity and ability to bind to other molecules. By tuning the phosphorylation state of proteins in the synaptic environment, PKCα may play an important role in synaptic function and neuronal signaling. To assess its role in AD, several research teams collaborated to first generate a mouse model with the PKCα M489V mutation and then assess its biochemistry and behavior over the next year and a half (corresponding to approximately 55 years in human aging). After three months, the brains of the mutated mice had significantly altered levels of protein phosphorylation compared to the brains of wild type control mice, indicating that neuronal proteins were being misregulated. By 4.5 months, the mice's hippocampal neurons showed several cellular changes, including synaptic depression and reduced density of dendritic spines. By 12 months, the mice showed impaired performance in behavioral tests of spatial learning and memory, clear evidence of cognitive decline. "We were surprised to find that just a slight increase in PKCα activity was enough to recreate the Alzheimer's phenotype in a mouse," said senior author Alexandra C. Newton, PhD, Distinguished Professor of Pharmacology at UC San Diego School of Medicine. "This is an amazing example of the importance of homeostasis in biology -- even minor tweaks in kinase activity can result in pathology if the effects are allowed to accumulate over a lifetime." To confirm whether similar enzymatic changes could be observed in human patients, the researchers also measured protein levels in the frontal cortex of human brains from deceased patients with AD and control individuals. Brains from AD patients showed a 20 percent increase in PKCα. Furthermore, phosphorylation of a known PKCα substrate was increased by approximately four-fold in these brains, further suggesting that PKCα activity was enhanced in the human AD brain. "The PKCα M489V mutation has been a great way to test the role of this enzyme in AD, but there are many other ways to have aberrant PKCα," said Newton. "We're finding that many mutations associated with AD are in genes that regulate PKCα, so a variety of gene variants may actually be converging onto this same important pathway." The authors note that several pharmacological inhibitors of PKCα have already been developed for use in cancer and could be repurposed to treat AD. Future drug development might focus on ways to selectively inhibit PKCα at the synapse. "It's increasingly clear that the amyloid plaques we see in AD are secondary to some other earlier process happening in the brain," said Newton. "Our findings add to a growing body of evidence that PKCα may be an important part of that process, and is a promising target for treating or preventing Alzheimer's disease." Co-authors include: Gema Lorden, Jacob M. Wozniak, Kim Dore, Laura E. Dozier, Gentry N. Patrick and David J. Gonzalez, all at UC San Diego; Amanda J. Roberts and Chelsea Cates-Gatto at The Scripps Research Institute; and Rudolph E. Tanzi at Harvard Medical School.

A multinational research collaboration has developed a new peptide dubbed “PATAS”, which appears to fix the metabolic abnormalities leading to type 2 diabetes (T2D). The research was coordinated by Vincent Marion, Ph.D., with France-based Inserm in collaboration with the University of Birmingham (UK), Monash University (Australia) and with Dr. Alexander Fleming, M.D., former senior endocrinologist at the U.S. Food and Drug Administration, and was published Wednesday in the journal Diabetes. Type 2 diabetes is marked by high glucose levels in the blood. Unlike type 1 diabetes, which is an autoimmune disease caused by the patient’s immune system attacking and destroying the pancreas cells that produce insulin, type 2 diabetes is the result of insulin resistance in cells in the body. The incidence of T2D has been increasing for decades because of the obesity epidemic and an aging population. Inserm notes that there “have been no disruptive therapeutic innovations to reach market in over a decade.” Obesity is connected to hypertrophic adipocytes (oversized fat cells), which leads to impaired glucose absorption. Adipocytes are key regulators of whole-body metabolic fitness because of how they control insulin sensitivity. The new research, conducted on animal models, demonstrated that PATAS (peptide derived from PKC alpha Targeting AlmS) restored glucose uptake in the fat cells (adipocytes), which treated insulin resistance while benefiting the entire body. Earlier research suggested that adipose tissue abnormalities caused by a dysfunctional protein, ALMS1, led to severe insulin resistance in people with Alstrom syndrome who had early-onset T2D. In animal models, fixing this protein within the adipocytes restored blood glucose balance. Alstrom syndrome is a rare disease that affects many systems throughout the body. It includes obesity, T2D, short stature, heart disease and a progressive loss of vision and hearing. It is caused by mutations in the ALMS1 gene. The researchers then turned their focus on ALMS1 and how it relates to other adipocyte proteins. They found that in the absence of insulin, ALMS1 binds to a protein dubbed PKC alpha. Insulin activation caused ALMS1 and PKC alpha to separate, allowing glucose to enter cells. But in people with T2D insulin resistance, the connection between the two proteins is maintained. “Thanks to PATAS, the adipocytes that could no longer access glucose were once again able to absorb it and then metabolize it in order to synthesize and secrete lipids which are beneficial to the entire body. These positive effects are visible in our animal models, with a marked improvement in insulin resistance. Other parameters and comorbidities are also improved, including better blood glucose control and decreased liver fibrosis and steatosis,” Marion stated. The next step is a clinical trial to evaluate PATAS in humans. The researchers say this class of antidiabetic drugs may be able to treat not only T2D but also other cardio-metabolic diseases where dysfunctional adipocytes and insulin resistance are a problem. The authors wrote, “In vivo, PATAS reduced whole-body insulin resistance, and improved glucose intolerance, fasting glucose, liver steatosis and fibrosis in rodents. Thus, PATAS represents a novel first-in-class peptide that targets the adipocyte to ameliorate insulin resistance and its associated comorbidities.” Currently, the most common treatments for T2D aside from weight loss and diet are glucagon-like peptide-1 (GLP-1) agonists, such as Eli Lilly’s Trulicity (dulaglutide), Novo Nordisk’s Victoza (liraglutide) and Ozempic (semaglutide).