MiRly regulating metabolism

In this issue of Blood, Tili et al identify an important link between microRNAs and the metabolic adaptation characteristic of cancer cells.¹  In chronic lymphocytic leukemia (CLL), the microRNA, miR-125b becomes down-regulated resulting in an increase in the expression and activity of a myriad of metabolic enzymes that promote metabolic reprogramming in a way that favors malignant transformation.

Cells normally generate the bulk of their energy (ATP) via mitochondrial oxidative phosphorylation and switch to glycolysis under anaerobic stress. Cancer cells, on the other hand, alter their metabolism to preferentially generate ATP via glycolysis, even in the presence of abundant oxygen, a phenomenon termed the “Warburg effect.”²  This adaptation, although inefficient, generates sufficient energy and, more importantly, ensures a steady supply of anabolic carbon and nitrogen that can be used to synthesize the nucleotides, amino acids, and lipids essential for tumorproliferation.²  MicroRNAs are master gene regulators whose expression is widely altered in cancers. They bind to multiple mRNAs in cells by sequence complementarity to negatively impact the expression of their target genes. Consequently, deregulation in the expression of even a single microRNA has widespread consequences on downstream gene and signaling cascades.³  Given their central role in biology, it is not at all surprising that alterations in microRNA expression would be pivotal in the metabolic reprogramming of tumor cells.⁴ 

CLL is a disease that takes an indolent course in some and aggressive in others.⁵  Here, Tili and colleagues demonstrate that miR-125b is expressed at low levels in both indolent and aggressive CLL.¹  Loss of this microRNA was functionally linked to the increased expression of a large number of transcripts that encoded for proteins within the lipid, phospholipid, carbohydrate, amino acid, or nucleotide metabolic pathways. This, in turn, led to a preference for aerobic glycoysis as manifested by the enhanced production of glycolytic intermediates, lactates, and other metabolites that could support anabolic growth. Conversely, overexpression of this microRNA reversed metabolic dependence on aerobic glycolysis. Thus, miR-125b may act as a gate keeper that prevents the establishment of the Warburg effect (see figure).

However, several key questions remain unanswered. First, miR-125b is located on chromosome 11, at the genomic location 11q24.1, which is close to that of the ATM gene (11q22-23). This locus is frequently deleted in CLL.⁶  However, the actual frequency with which deletions in 11q extend into the miR-125b gene has not been evaluated. Under these circumstances, could there be alternative mechanisms that account for the low levels of expression of miR-125b in CLL? Second, CLL is a quiescent disease with a very low proliferative index; the majority of neoplastic B lymphocytes accumulate due to enhanced survival caused by defects in apoptotic pathways. If this is the case, why do CLL cells undergo metabolic adaptation toward proliferation? Third, is the loss of miR-125b and establishment of the Warburg effect alone sufficient for malignant transformation? Finally, does loss of miR-125b enable the proliferative fraction in CLL?

In addition to miR-125b, other microRNAs as well as protein coding genes are also known to be critical for the establishment of metabolic adaptations and tumorigenesis. In fact, recent evidence indicates that the fundamental objective of alterations in proto-oncogene and tumor-suppressor genes is the reprogramming of cellular metabolism.⁷  Multiple microRNAs directly or indirectly regulate key proteins responsible for metabolic reprogramming.⁴  Similarly, master regulators such as PI3K, Akt, c-myc, and HIF1 along with their downstream signaling pathways are all well known to facilitate metabolic adaptations to support tumor growth.^8,9  It would be important to understand the consequences of miR-125b dysregulation on metabolic adaptation within the context of the other regulators of the Warburg adaptation.