ADIPONECTIN AND LEPTIN: NOVEL PROLIFERATIVE AND METABOLIC FEATURES FOR CANCER THERAPEUTICS

Cancer progression and therapeutic resistance are increasingly recognised as processes influenced by metabolic dysregulation and adipokine-mediated signalling. Among adipose- derived factors, adiponectin and leptin play opposing roles in tumorigenesis, modulating cancer cell growth, metabolism, and response to therapy. This thesis investigates the functional impact of adipokine signalling in lung and prostate cancers, with a focus on adiponectin receptor agonist AdipoRon activation and leptin-driven oncogenic crosstalk. In non-small-cell lung cancer (NSCLC), activation of adiponectin receptors by the synthetic agonist AdipoRon exerted marked antiproliferative effects, significantly reducing cell viability, growth, and clonogenic capacity through cell cycle deceleration. These effects were accompanied by a metabolic reprogramming towards enhanced glycolysis, characterised by increased glucose consumption and lactate production. AMP-activated protein kinase (AMPK) emerged as a central mediator of AdipoRon activity, as pharmacological inhibition of AMPK significantly attenuated its anticancer efficacy. Moreover, interference with glycolytic flux further potentiated AdipoRon-induced growth suppression. Importantly, combining AdipoRon with the chemotherapeutic agent paclitaxel resulted in synergistic antitumour effects, including enhanced apoptosis and reduced clonogenic survival. This combination therapy was dependent on AMPK activation and partially involved modulation of ERK1/2 signalling, highlighting adiponectin receptor agonism as a promising strategy to improve NSCLC treatment outcomes. Conversely, in prostate cancer (PCa), leptin signalling promoted tumour progression, particularly in androgen-independent disease. Leptin selectively enhanced proliferation and survival in androgen-independent PCa cells through the upregulation of insulin-like growth factor binding protein 2 (IGFBP2). Silencing of IGFBP2 abrogated leptin-induced tumour growth, identifying IGFBP2 as a critical mediator of leptin-driven oncogenic effects. Clinically, elevated IGFBP2 expression in PCa tissues and its association with obesity-related parameters further supported the relevance of leptin–IGFBP2 signalling in aggressive disease. Collectively, these findings delineate divergent yet interconnected roles of adipokines in cancer, demonstrating the tumour-suppressive potential of adiponectin receptor agonist AdipoRon activation and the tumour-promoting, resistance-driving effects of leptin signalling. Targeting adipokine-mediated metabolic pathways may therefore represent a valuable therapeutic avenue to counteract cancer progression and overcome treatment resistance in obesity-associated malignancies.