Therapeutic targeting of cancer cell metabolism

Abstract

In 1927, Otto Warburg and coworkers reported the increased uptake of glucose and production of lactate by tumors in vivo as compared with normal tissues. This phenomenon, now known as the Warburg effect, was recapitulated in vitro with cancer tissue slices exhibiting excessive lactate production even with adequate oxygen. Warburg's in vivo studies of tumors further suggest that the dependency of tumors in vivo on glucose could be exploited for therapy, because reduction of arterial glucose by half resulted in a four-fold reduction in tumor fermentation. Recent work in cancer metabolism indicates that the Warburg effect or aerobic glycolysis contributes to redox balance and lipid synthesis, but glycolysis is insufficient to sustain a growing and dividing cancer cell. In this regard, glutamine, which contributes its carbons to the tricarboxylic acid (TCA) cycle, has been re-discovered as an essential bioenergetic and anabolic substrate for many cancer cell types. Could alterations in cancer metabolism be exploited for therapy? Here, we address this question by reviewing current concepts of normal metabolism and altered metabolism in cancer cells with specific emphasis on molecular targets involved directly in glycolysis or glutamine metabolism.

Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration

“…Glucose and oxygen deprivation is further relevant to cancer therapy 28 and the primary aim of antiangiogenic and antivascular treatments. According to our in vitro results (Figure 1 and Supplementary Figure 5), limited glucose availability can stabilize MCT1-CD147 complexes in a dosedependent manner and, consequently, promotes MCT1-dependent TC migration ( Figure 6).…”

Glioblastoma: Current Chemotherapeutic Status and Need for New Targets and Approaches

“…The recent "renaissance of the Warburg Hypothesis" (Warburg et al, 1927, Warburg, 1956) has stimulated a new era in elucidating the aggressive nature of many malignant tumors (including glioblastoma) and their purported dependence on glycolysis for energy and survival (Bhardwaj et al, 2010;Lino & Merlo, 2009;Ordys et al, 2010;Semenza, 2011;Stegh et al, 2008). While numerous studies have documented mutations in mitochondrial DNA (mtDNA) in a variety of cancers (Czarnecka & Bartnik, 2009) can thus tentatively provide a mechanistic connection to dysfunctional mitochondrial oxidative metabolism as predicted by the Warburg hypothesis, other recent evidence suggests this aspect of the Warburg hypothesis requires critical re-appraisal (Bayley & Devilee, 2010;Dang et al, 2011;Frezza et al, 2011;Ordys et al, 2010;Srivastava & Moraes, 2009). The aspect of the Warburg hypothesis emphasizing dysfunctional mitochondrial oxidative metabolism in cancer cells deserves a critical re-appraisal because recent studies on cancer cell metabolism have uncovered new mechanistic roles for mTOR and p53.…”

“…However, there are some known but complex cross-talks between the signaling pathways regulated by mTOR and p53 (Maddocks & Vousden, 2011): nevertheless, whether the interactions between mTOR and p53 signaling favor glioblastoma cell growth and proliferation remains to be fully elucidated. Some recent cancer cell metabolism studies have further challenged the reliance of cancer cells on glycolysis for energy production and lipid synthesis: in fact, such studies have argued that glycolysis alone is inadequate to maintain the metabolic needs of growing and actively dividing cancer cells (Dang et al, 2011;Maddocks & Vousden, 2011;Shanware et al, 2011). Thus, many researchers have re-discovered the importance of glutamine in meeting the inadequacy of glycolysis to fuel growth and proliferation of many cancer types including gliomas (Dang et al, 2011;Maddocks & Vousden, 2011;Shanware et al, 2011).…”

A return to cancer metabolism

“…The last several years have witnessed a dramatic resurgence of interest in the role of metabolic reprogramming in cancer progression. In this issue of the Journal of Molecular Medicine, we present five outstanding reviews [3][4][5][6][7] by leaders in the field of cancer metabolism, who summarize recent findings regarding key biochemical pathways and critical pathway regulators, which provide new insights into cancer progression and new targets for cancer therapy.…”

“…Chi Dang (Johns Hopkins University, Baltimore USA) and colleagues begin by discussing the highly variable nature of the metabolic profiles of normal cells and tissues [3]. These physiological profiles are then contrasted with the reprogramming of glucose metabolism that occurs in cancer cells, which is often referred to as the Warburg phenomenon.…”