Sara Marchesi

Aberrant activation of the PI3K/Akt pathway commonly occurs in cancers and correlates with multiple aspects of malignant progression. In particular, recent evidence suggests that the PI3K/Akt signaling plays a fundamental role in promoting the so-called aerobic glycolysis or Warburg effect, by phosphorylating different nutrient transporters and metabolic enzymes, such as GLUT1, HK2, PFKB3/4 and PKM2, and by regulating various molecular networks and proteins, including mTORC1, GSK3, FOXO transcription factors, MYC and HIF-1α. This leads to a profound reprogramming of cancer metabolism, also impacting on pentose phosphate pathway, mitochondrial oxidative phosphorylation, de novo lipid synthesis and redox homeostasis and thereby allowing the fulfillment of both the catabolic and anabolic demands of tumor cells. The present review discusses the interactions between the PI3K/Akt cascade and its metabolic targets, focusing on their possible therapeutic implications.

Melanoma is the most aggressive and deadly form of skin cancer. However, advances in the understanding of its biology have led to the development of several new therapeutic approaches. One of these novel treatment strategies is based on the targeting of the mitochondrial bioenergetic and networks responsible for tumor initiation and progression. Indeed, it has recently emerged that changes in mitochondrial metabolism, dynamics, redox homeostasis, and apoptosis are strictly associated with tumor growth, metastasis, and drug resistance. In this review, we summarize current evidence about the multiple biological functions exerted by mitochondria in melanoma, also focusing on the role of these organelles as promising targets for pharmacological intervention.

Prostate cancer (PCa) is one of the most commonly diagnosed malignancies and main causes of cancer-related deaths worldwide. It is characterized by high heterogeneity, ranging from slow-growing tumor to metastatic disease. Since both therapy selection and outcome strongly rely on appropriate patient stratification, it is crucial to differentiate benign from more aggressive conditions using new and improved diagnostic and prognostic biomarkers. Extracellular vesicles (EVs) are membrane-coated particles carrying a specific biological cargo composed of nucleic acids, proteins, and metabolites. Here, we provide an overview of the role of EVs in PCa, focusing on both their biological function and clinical value. Specifically, we summarize the oncogenic role of EVs in mediating the interactions with PCa microenvironment as well as the horizontal transfer of metastatic traits and drug resistance between PCa cells. Furthermore, we discuss the potential usage of EVs as innovative tools for PCa diagnosis and prognosis.

Many tumors consist of heterogeneous cell populations derived from a minority of cancer stem cells (CSCs), which possess distinct metabolic profiles that contribute to resistance against conventional anticancer therapy and increase the risk of tumor relapse. These unique CSC phenotypes are largely supported by altered mitochondrial function and turnover, regulated through continuous cycles of mitochondrial biogenesis, fission, fusion, and mitophagy. Consequently, understanding mitochondrial regulatory mechanisms in CSCs could reveal novel targets for cancer therapy. This article explores how mitochondrial dynamics contribute to CSC metabolic adaptation and drug resistance, alongside recent advances in the development of mitochondria-targeted drugs and their therapeutic usage. • Cancer stem cells are a cellular subpopulation involved in tumor aggressiveness. • They display deregulated mitochondrial mass due to changes in PGC1-α and mtDNA levels. • Mitochondrial fission and fusion proteins are overexpressed in these cells. • Mitophagy supports their self-renewal abilities and intrinsic chemoresistance. • Targeting mitochondrial dynamics represents a novel strategy for cancer eradication.

There is consistent evidence of an association between obesity and the risk of prostate cancer (PCa). A crosstalk between PCa and adipocytes has been highlighted; however, the role of extracellular vesicles (EVs) in this communication still needs to be elucidated. Herein, we demonstrated that PCa EVs can trigger lipolysis in 3T3-L1 adipose cells, by downregulating G0/G1 switch protein 2 (G0S2), inducing adipose triglyceride lipase (ATGL) expression and activating the cyclic AMP (cAMP)/protein kinase A (PKA)/hormone-sensitive lipase (HSL) signaling pathway. Interestingly, we showed that the free fatty acids (FFAs) released from the EV-treated adipocytes could increase PCa cell proliferation and clonogenic ability. Moreover, they promoted tumor cell migration and invasion, while parallelly reducing the induction of anoikis. Mechanistically, FFAs were found to trigger Akt activation, and pharmacological inhibition of this protein by BEZ235 could successfully counteract their cancer-promoting effects. Collectively, these results support the presence of an EV-driven bidirectional interplay between PCa cells and adipocytes, which reprograms the latter toward a lipolytic, tumor-promoting phenotype.