Non-canonical roles for metabolic enzymes and intermediates in malignant progression and metastasis

Abstract

Metabolic alterations are established as a hallmark of cancer. Such hallmark changes in cancer metabolism are characterized by reprogramming of energy-producing pathways and increases in the generation of biosynthetic intermediates to meet the needs of rapidly proliferating tumor cells. Various metabolic phenotypes such as aerobic glycolysis, increased glutamine consumption, and lipolysis have also been associated with the process of metastasis. However, in addition to the energy and biosynthetic alterations, a number of secondary functions of enzymes and metabolites are emerging that specifically contribute to metastasis. Here, we describe atypical intracellular roles of metabolic enzymes, extracellular functions of metabolic enzymes, roles of metabolites as signaling molecules, and epigenetic regulation mediated by altered metabolism, all of which can affect metastatic progression. We highlight how some of these mechanisms are already being exploited for therapeutic purposes, and discuss how others show similar potential.

Nuclear control of lung cancer cells migration, invasion and bioenergetics by eukaryotic translation initiation factor 3F

“…In particular, there are recent publications supporting that increased expression of EMT-linked transcription factors such as Snail and Twist causes reduced oxidative metabolism [31,32], and that mitochondrial dysfunction induces invasive phenotype in lung cancer [33], in contrast with our findings. Accordingly, in a recent review article, Williams and Fingleton [34] wrote that 'Various metabolic phenotypes such as aerobic glycolysis, increased glutamine consumption, and lipolysis' have been associated with the process of metastasis' [34]. In fact, several determinants as the oncogenic profile, composition of the serum and the metastatic niche, patients nutritive diet, microbiota composition, primary tumor localization, and tumor history in terms of treatments, age of the patient at tumor diagnosis and smoking history will impact the bioenergetic profile of cancer cells and metastatic ones.…”

Assessment of biochemical recurrence of prostate cancer (Review)

“…While a variety of tumor properties have been examined for prognostic purposes, the stromal contributions and the communications between he stroma and tumor have not been actively determined for biomarker purposes. A potential mechanism causing stromal alterations is through PC-associated metabolic reprogramming, which results in the accumulation of metabolic intermediates (267); these materials affect gene expression via epigenetic alterations (268). Metabolic reprogramming is a well-established mechanism supporting not only tumorigenesis, but also cancer progression (36,267,268).…”

“…A potential mechanism causing stromal alterations is through PC-associated metabolic reprogramming, which results in the accumulation of metabolic intermediates (267); these materials affect gene expression via epigenetic alterations (268). Metabolic reprogramming is a well-established mechanism supporting not only tumorigenesis, but also cancer progression (36,267,268). In this regard, PC-associated metabolic alterations will have a prognostic potential which has been recently reviewed by Lucarelli et al (267).…”

Dichloroacetate (DCA) and Cancer: An Overview towards Clinical Applications

“…Too many factors are responsible for therapy failure or relapse, so there is an urgent need to find new approaches to treat it. Apart from the typical well-known properties featuring malignant cells, including abnormal proliferation, deregulation of apoptosis, and cell cycle [1, 2], cancer cells also display a peculiar metabolic machine that offers a further promising approach for cancer therapy [3–5]. Our group had already suggested the importance of a metabolic characterization of cancer cells to predict the efficacy of a metabolic treatment [6].…”