Protein kinase D: Integrating cancer and metabolic disorders

Abstract

Obesity and type II diabetes mellitus (T2DM) are intricately linked to elevated cancer risk. Protein Kinase D (PKD) isoforms (PKD1, PKD2, and PKD3) have emerged as pivotal mediators at the centre of metabolic and oncogenic signalling. This review discusses isoform-specific roles of PKDs in the pathophysiology of both metabolic disorders and tumour progression. PKD1 exhibits a context-dependent dual role in cancer, acting as a tumour suppressor by reinforcing epithelial adhesion and restricting invasion in several carcinomas, yet exerting pro-tumorigenic effects in specific tissues such as the pancreas and skin. Metabolically, PKD1 supports insulin secretion in pancreatic β cells while promoting adipocyte lipogenesis and suppressing thermogenesis, mechanisms that contribute to systemic insulin resistance and may prime the tumour microenvironment. PKD2 promotes tumour progression through sustained hypoxia signalling, matrix remodelling, and immune evasion, driven by its regulation of HIF-1α, Snail, β-catenin, and PD-L1. PKD3 facilitates oncogenic proliferation and metabolic rewiring, particularly enhancing glycolysis via the p65/PFKFB3 axis and modulating insulin/glucagon signalling in hepatocytes. Obesity- or diabetes-related factors, such as diacylglycerol, leptin, and pro-inflammatory cytokines, enhance PKD signalling across tissues, reinforcing its role in connecting metabolic disorders to cancer. These findings highlight PKD isoforms as potential therapeutic targets, particularly in cancer settings where metabolic dysfunction plays a contributing role. While current PKD inhibitors lack isoform specificity, future therapeutic strategies focused on PKD2 and PKD3 modulation may offer selective control over invasion, immune evasion, and metabolic reprogramming in metabolically comorbid cancer patients.