Author Correction: Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin

DeWaal, Dannielle C.; Nogueira, Véronique; Terry, Alexander R.; Patra, Krushna C.; Jeon, Sang‐Min; Guzman, Grace; Au, Jennifer; Long, Christopher P.; Antoniewicz, Maciek R.; Hay, Nissim

doi:10.1038/s41467-018-04182-z

Cited by 29 publications

(21 citation statements)

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“…Accordingly, the drug combination reduced the expression of HK2, PFKP, and MCT4 in HepG2 cells, and significantly decreased the ECAR under both normoxia and hypoxia/CoCl 2 treatment, even though no further enhancements were promoted in comparison with single treatments. The relevance of targeting these genes finds support in previous studies demonstrating their key role in HCC tumor growth (44,75,76).…”

Section: Discussionmentioning

confidence: 67%

“…Under normoxic conditions, both palbociclib and regorafenib as well as their combination down-regulated the expression of hexokinase 2 (HK2), the major HK isoform expressed in HCC (44), and phosphofructokinase platelet (PFKP), a major isoform of PFK-1 controlling the first rate-limiting step of glycolysis in cancer cells (45) (Figure 7C). Under hypoxic conditions, both genes were significantly down-regulated by regorafenib and no further decrease was induced by the combination.…”

Section: Effects Of the Simultaneous Combination Of Palbociclib With mentioning

confidence: 99%

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Simultaneous Combination of the CDK4/6 Inhibitor Palbociclib With Regorafenib Induces Enhanced Anti-tumor Effects in Hepatocarcinoma Cell Lines

et al. 2020

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Advanced hepatocarcinoma (HCC) is an aggressive malignancy with poor prognosis and limited treatment options. Alterations of the cyclin D-CDK4/6-Rb pathway occur frequently in HCC, providing the rationale for its targeting at least in a molecular subset of HCC. In a panel of HCC cell lines, we investigated whether the CDK4/6 inhibitor palbociclib might improve the efficacy of regorafenib, a powerful multi-kinase inhibitor approved as second-line treatment for advanced HCC after sorafenib failure and currently under clinical investigation as first-line therapy in combination with immunotherapy. In Rb-proficient cells, the simultaneous drug combination, but not the sequential schedules, inhibited cell proliferation, either in short or in long-term experiments, and induced cell death more strongly than individual treatments. Moreover, the combination significantly reduced spheroid cell growth and inhibited cell migration/invasion. The superior efficacy of palbociclib plus regorafenib emerged also under hypoxia and was associated with a significant down-regulation of CDK4/6-Rb-myc and mTORC1/p70S6K signaling. Moreover, regorafenib suppressed palbociclib-induced expression of cyclin D1 contributing to the cytotoxic effects of the combination. Besides these inhibitory effects on cell viability/proliferation, palbociclib and regorafenib reduced glucose uptake, although this effect was dependent on the cell model and on the oxygen availability (normoxia or hypoxia). Palbociclib and regorafenib combination impaired glucose uptake and utilization, down-regulating basal and hypoxia-induced expression of HIF-1α, HIF-2α, GLUT-1, and MCT4 proteins as well as the activity/expression of glycolytic enzymes (HK2, PFKP, aldolase A, PKM2). In addition, regorafenib alone reduced mitochondrial respiration. The combined treatment impaired glucose metabolism and respiration without enhancing the effects of the single agents. Our findings provide pre-clinical evidence for the effectiveness of palbociclib and regorafenib combination in HCC cell models.

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Section: Discussionmentioning

confidence: 67%

Section: Effects Of the Simultaneous Combination Of Palbociclib With mentioning

confidence: 99%

Simultaneous Combination of the CDK4/6 Inhibitor Palbociclib With Regorafenib Induces Enhanced Anti-tumor Effects in Hepatocarcinoma Cell Lines

et al. 2020

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“…Hexokinases are enzymes that phosphorylate glucose to produce glucose-6-phosphate, which is the first step in most glucose pathways, including glycolysis. Hexokinase 2 (HK2) is the major isoform that is overexpressed in cancers (218) and its depletion can ameliorate the outcomes in a model of hepatocellular carcinoma (219). There are some indications that, under hypoxic conditions, the overexpression of HK2 can facilitate EMT (220).…”

Section: Glycolysismentioning

confidence: 99%

EMT Factors and Metabolic Pathways in Cancer

Georgakopoulos-Soares

et al. 2020

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The epithelial-mesenchymal transition (EMT) represents a biological program during which epithelial cells lose their cell identity and acquire a mesenchymal phenotype. EMT is normally observed during organismal development, wound healing and tissue fibrosis. However, this process can be hijacked by cancer cells and is often associated with resistance to apoptosis, acquisition of tissue invasiveness, cancer stem cell characteristics, and cancer treatment resistance. It is becoming evident that EMT is a complex, multifactorial spectrum, often involving episodic, transient or partial events. Multiple factors have been causally implicated in EMT including transcription factors (e.g., SNAIL, TWIST, ZEB), epigenetic modifications, microRNAs (e.g., miR-200 family) and more recently, long non-coding RNAs. However, the relevance of metabolic pathways in EMT is only recently being recognized. Importantly, alterations in key metabolic pathways affect cancer development and progression. In this review, we report the roles of key EMT factors and describe their interactions and interconnectedness. We introduce metabolic pathways that are involved in EMT, including glycolysis, the TCA cycle, lipid and amino acid metabolism, and characterize the relationship between EMT factors and cancer metabolism. Finally, we present therapeutic opportunities involving EMT, with particular focus on cancer metabolic pathways.

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“…In contrast, the pyruvate dehydrogenase levels was higher in SEMA3F KD groups, but Pyruvate kinase isozymes M2(PKM2) expression levels was not difference between two groups. These results suggested that level of aerobic glycolysis of LECs in SEMA3F KD groups was lower than that in control groups in hypoxia, it converted glycolysis to the Krebs cycle was not be blocked(Liu et al ,2017;DeWaal et al ,2018; Sukonina et al ,2019). To further determination the efficacy to knock down SEMA3F of CRCs inhibition glycolysis of hLECs in hypoxia, therefore, we use 3-bromopyruvate to inhibit the glycolysis of the two groups.…”

Section: Resultsmentioning

confidence: 83%

SEMA3F-deficient colorectal cancer cells Promote lymphangiogenesis: fatty acid metabolism replace glycolysis for energy supply during lymphatic endothelial cells proliferation in tumor hypoxia microenvironment

Tao

et al. 2019

Preprint

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22 30 tubulogenesis capacity and hLECs migration were escalated in the 31 hypoxia, the hLECs mainly relied on fatty acid metabolism not aerobic 32 glycolysis during lymphangiogenesis. SEMA3F-deficient CRCs 33 up-regulated PMAKP expression and phosphorylation of hLECs, and 34 activated its peroxisome proliferator-activated receptor (PPARs) and 35 Peroxisome proliferator-activated receptor gamma coactivator-1 alpha 36 (PGC-1a) facilitated their switched toward fatty acids (FA) catabolism. 37Furthermore, we observed that activation of the PGCI-PPAR lipid 38 oxidation signaling pathway in hLECs was caused by the secretion of 39 interleukin-6 by tumor cells.Taken together, this study indicates that 40 CRCs with SEMA3F expression depletion significantly promotes 41 lymphangiogenesis in hypoxia and faciliates the secretion of IL-6 in 42 tumor cell, and activates mitochondria fatty acids oxidation (FAO) 43 reaction in the hLECs by PGCI-PPAR signaling pathways to support its 44 growth. 45 46 acid metabolism; hypoxia 48 49 104 CRCs promotion hLECs lipid metabolism and lymphangiogenesis under 105 hypoxemia.We demonstrated that SEMA3F plays a crucial role in hLECs 106 energy metabolism. CRCs with SEMA3F expression depletion 107 significantly promotes hLECs migration and tubulogenesis capacity in 108 hypoxia, and enhance the lipid metabolism via suppressing aerobic 109 glycolysis of hLECs, and the lipid metabolism to induce the PGCI-PPAR 110 signaling pathway in hLECs. Further evidence demonstrated that CRCs 111 cell with SEMA3F expression depletion up-regulated its IL-6 secretion, 112 to activate the PGCI-PPAR signaling pathway and induces the lipid 113 metabolismin of hLECs in hypoxia. Our findings for the first time 114 revealed a novel role and the underlying mechanism, the CRCs cell with 115 SEMA3F expression deficiency was involved the energy metabolism 116 with hLECs in the hypoxia environment, and induce tumor 117 lymphangiogenesis of CRCs to promote lymphatic metastasis. 118 119 Result 120 1.SEMA 3F-deficient CRCs further enhance lymphangiogenesis 121 under hypoxic conditions 122 In our previous study, loss of SEMA3F expression, the inhibitory ligand 123 of NRP2, critically contributes to CRCs metastasis and 124 lymphangiogenesis in normoxia(Wu et al, 2011; Ou et al, 2015). To 125 examine whether SEMA3F loss expression plays any roles in induce 126 lymphangiogenesis of colorectal cancer cell in hypoxia, We used 127 supernatants of the colorectal adenocarcinoma cell line HCT116 with 128 SEMA3F expression and SEMA3F knockout (SEMA3F KD), to culture 129 hLECs three-dimensionally on matrigel substrate under normoxia and 130 hypoxia to induce tubule formation of hLECs. The tubulogenesis of 131 hLECs was improved in hypoxia than that in normoxia (p < 0.001; Figure 132 1A and B). Strikingly, comparing with control cells, SEMA3F KD groups 133 displayed significantly enhancement of tubulogenesis ability of hLECs 134 under normoxic conditions. Consistent with normoxic conditions 135 culture, SEMA3F KD groups had stronger abili...

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Author Correction: Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin

Cited by 29 publications

References 0 publications

Simultaneous Combination of the CDK4/6 Inhibitor Palbociclib With Regorafenib Induces Enhanced Anti-tumor Effects in Hepatocarcinoma Cell Lines

Simultaneous Combination of the CDK4/6 Inhibitor Palbociclib With Regorafenib Induces Enhanced Anti-tumor Effects in Hepatocarcinoma Cell Lines

EMT Factors and Metabolic Pathways in Cancer

SEMA3F-deficient colorectal cancer cells Promote lymphangiogenesis: fatty acid metabolism replace glycolysis for energy supply during lymphatic endothelial cells proliferation in tumor hypoxia microenvironment

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