Therapeutic Metabolic Reprograming Using microRNAs: From Cancer to HIV Infection

Abstract

MicroRNAs (miRNAs) are crucial regulators of cellular processes, including metabolism. Attempts to use miRNAs as therapeutic agents are being explored in several areas, including the control of cancer progression. Recent evidence suggests fine tuning miRNA activity to reprogram tumor cell metabolism has enormous potential as an alternative treatment option. Indeed, cancer growth is known to be linked to profound metabolic changes. Likewise, the emerging field of immunometabolism is leading to a refined understanding of how immune cell proliferation and function is governed by glucose homeostasis. Different immune cell types are now known to have unique metabolic signatures that switch in response to a changing environment. T-cell subsets exhibit distinct metabolic profiles which underlie their alternative differentiation and phenotypic functions. Recent evidence shows that the susceptibility of CD4+ T-cells to HIV infection is intimately linked to their metabolic activity, with many of the metabolic features of HIV-1-infected cells resembling those found in tumor cells. In this review, we discuss the use of miRNA modulation to achieve metabolic reprogramming for cancer therapy and explore the idea that the same approach may serve as an effective mechanism to restrict HIV replication and eliminate infected cells.

Immunometabolism, extracellular vesicles and cardiac injury

“…Metabolic reprogramming requires finely tuned activation and simultaneous repression of multiple cell signaling pathways, metabolites, and genes that can be regulated by multiple miRNAs ( 34 ). Activation of HIF-1α is recognized as a critical mediator of glycolytic reprogramming, while AMPK is a major regulator of reprogramming to OXPHOS metabolism ( 34 , 35 ). Several miRNAs that regulate inflammation also regulate HIF-1α and several glycolytic enzymes.…”

Metabolism of NK cells during viral infections

“…On the other hand, the metabolic defects present in NK cells could be regulated by miRNAs to improve their cytotoxic function against infected cells. Several miRNAs have been reported to repress key steps in the glycolytic pathway, which could be identified as potential therapeutic agents ( Figure 2 ) ( 115 ). Therefore, metabolism modulation is proposed as a therapeutic to improve NK cell cytotoxicity in viral infections ( 116 ).…”

Metabolic reprogramming by miRNAs in the tumor microenvironment: Focused on immunometabolism

“…On the other hand, tumor cells absorb glucose and glutamine from the extracellular media due to mutations in key metabolic regulatory genes, including c-MYC, AKT, and PI3K ( 31 ). Modifications in the function of these and other genes cause cell-autonomous increases in the abundance and the function of membrane transporters and metabolic enzymes, allowing for increased glycolysis and glutaminolysis in the absence of external stimuli ( 33 ). This allows efficient coupling of energy and biosynthesis requirements for uncontrolled cell growth.…”

“…Modulatory connections are represented by referring arrowheads, whereas repressive interactions are represented by inhibiting arrows. The designations of pathways and metabolites are emphasized in bold and thicker lines to indicate their predominance in each condition ( 33 ). miRNA, microRNA ; HK, Hexokinase; LDHA, lactate dehydrogenase A; HIF1, Hypoxia-inducible factor 1.…”