Breast cancer stem cells rely on fermentative glycolysis and are sensitive to 2-deoxyglucose treatment

Abstract

A number of studies suggest that cancer stem cells are essential for tumour growth, and failure to target these cells can result in tumour relapse. As this population of cells has been shown to be resistant to radiation and chemotherapy, it is essential to understand their biology and identify new therapeutic approaches. Targeting cancer metabolism is a potential alternative strategy to counteract tumour growth and recurrence. Here we applied a proteomic and targeted metabolomic analysis in order to point out the main metabolic differences between breast cancer cells grown as spheres and thus enriched in cancer stem cells were compared with the same cells grown in adherent differentiating conditions. This integrated approach allowed us to identify a metabolic phenotype associated with the stem-like condition and shows that breast cancer stem cells (BCSCs) shift from mitochondrial oxidative phosphorylation towards fermentative glycolysis. Functional validation of proteomic and metabolic data provide evidences for increased activities of key enzymes of anaerobic glucose fate such as pyruvate kinase M2 isoform, lactate dehydrogenase and glucose 6-phopshate dehydrogenase in cancer stem cells as well as different redox status. Moreover, we show that treatment with 2-deoxyglucose, a well known inhibitor of glycolysis, inhibits BCSC proliferation when used alone and shows a synergic effect when used in combination with doxorubicin. In conclusion, we suggest that inhibition of glycolysis may be a potentially effective strategy to target BCSCs.

FASNating Targets of Metformin in Breast Cancer Stem-Like Cells

“…One study used a proteomics approach to determine that breast CSC rely on glycolysis more than differentiated breast cancer cells [8], which is consistent with observations made in noncancer stem cells. A different group demonstrated elevated glucose consumption and ATP levels, reduced lactate production, and a greater reliance on mitochondrial respiration in breast CSC compared to differentiated cells, indicating the absence of the classic Warburg phenotype [38].…”

Metabolic control of cancer cell stemness: Lessons from iPS cells

“…A recent proteomic and targeted metabolomic analysis of the main differences between breast CSC and their differentiated counterparts has identified a metabolic phenotype associated with the stem-like condition, indicating that breast CSC shift from mitochondrial OXPHOS toward fermentative glycolysis. 64 Of note, whereas the treatment of fibroblasts undergoing nuclear reprogramming with 2-deoxyglucose (2DG), a general inhibitor of glycolysis, blunted the generation of iPS cells, 36 2DG treatment inhibited breast CSC proliferation, thus revealing how the glycolytic requirement for iPS generation may be a potentially effective strategy to target breast CSCs. 64 Second lesson: Redox regulation Beyond the activation of multiple, redundant mechanisms limiting energy production by OXPHOS in preference to glycolysis and its biosynthetic pathway branches (e.g., the pentose phosphate pathway), the cellular redox state also impacts the balance between differentiated and stem cellular states.…”

Cancer metabolism in space and time: Beyond the Warburg effect

“…In can cer, it is cur rently thought that EMT is a crit i cal event to pro duce a metasta tic form of ep ithe lial can cer. Mes enchy mal cells show a meta bolic sig na ture char ac ter ized by the di ver sion of glu cose from gly col y sis to the TCA cy cle for ATP and glu ta mate pro duc tion [202,203], and to the hex osamine biosyn thetic path way for the post trans la tional mod i fi ca tion of gly co pro teins and Snail 1 [204][205][206]. In ter est ingly, emerg ing ev i dence re ported the role of on cometabo lites suc ci nate, fu marate and D 2 hy drox yg lu tarate de rived from TCA cy cle as mod u la tors of epi ge netic dys reg u la tion dri ving the EMT process.…”

“…For ex am ple, a sub set of pu ta tive ovar ian can cer stem cells (CD44 My D88 ) has been found to dis play a gly colytic meta bolic pro file over OX PHOS for their ATP gen er a tion [205], and a sub set of breast can cer cells able to grow as spheres in creas ingly rely on aer o bic gly col y sis and PPP flux com pared to the same cells grown in ad her ent con di tions [206]. Also, mod u la tion of spe cific gly colytic en zymes (i.e., de creased ex pres sion and ac tiv ity of pyru vate de hy dro ge nase or in creased ex pres sion or ac tiv ity of lac tate de hy dro ge nase A [LDHA]) plays a crit i cal role in pro mot ing the pro gly colytic phe no type of CICs in breast tu mors [237] and CSCs in lung tu mors [238].…”