Targeting Energy Metabolism in Cancer Treatment

Kubik, Joanna; Humeniuk, Ewelina; Adamczuk, Grzegorz; Madej-Czerwonka, Barbara; Korga-Plewko, Agnieszka

doi:10.3390/ijms23105572

Cited by 16 publications

(4 citation statements)

References 402 publications

(457 reference statements)

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“…Herein, by using a multi-omics approach, we demonstrate that the ability of H460 LUAD and MCF7 breast cancer cells to grow in non-adherent condition and to generate 3D tumor spheroids both in glucose-rich (3D_SM) and glucose-deprived (3D_FBS low ) culture media is associated with a consistent modulation of genes and proteins mainly involved in metabolic reprogramming towards an enhanced glycolytic phenotype most likely induced by a hypoxic condition. Indeed, we found that all the transitions from 2D to 3D cultures, regardless of the cancer cell type and cell culture conditions, are accompanied by the signi cant up-regulation of genes encoding for 6 out of 10 glycolytic enzymes: HK2 and ALDOC belonging to the energy-requiring phase and GAPDH, PGK1, ENO2, and PKM belonging to the energyreleasing phase [79]. In agreement with transcriptomic data, our metabolomic analyses highlighted a signi cant consumption of glucose and a corresponding increase in lactate production in all 3D tumor spheroids compared to their relative 2D parental cells, even within glucose-restricted culture conditions.…”

Section: Discussionmentioning

confidence: 91%

ALDOC- and ENO2- driven glucose metabolism sustains 3D tumor spheroids growth regardless of nutrient environmental conditions: a multi-omics analysis

Vitis

Battaglia

Pallocca

et al. 2022

Preprint

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Background Metastases are the major cause of cancer-related morbidity and mortality. By the time cancer cells detach from their primary site to eventually spread to distant sites, they need to acquire the ability to survive in non-adherent conditions and to proliferate within a new microenvironment in spite of stressing conditions that may severely constrain the metastatic process. In this study, we gained insight into the molecular mechanisms allowing cancer cells to survive and proliferate in an anchorage-independent manner, regardless of both tumor-intrinsic variables and nutrient culture conditions. Methods 3D spheroids derived from lung adenocarcinoma (LUAD) and breast cancer cells were cultured in either nutrient-rich or -restricted culture conditions. A multi-omics approach, including transcriptomics, proteomics, and metabolomics, was used to explore the molecular changes underlying the transition from 2D to 3D cultures. Small interfering RNA-mediated loss of function assays were used to validate the role of the identified differentially expressed genes and proteins in H460 and HCC827 LUAD as well as in MCF7 and T47D breast cancer cell lines. Results We found that the transition from 2D to 3D cultures of H460 and MCF7 cells is associated with significant changes in the expression of genes and proteins involved in metabolic reprogramming. In particular, we observed that 3D tumor spheroid growth implies the overexpression of ALDOC and ENO2 glycolytic enzymes concomitant with the enhanced consumption of glucose and fructose and the enhanced production of lactate. Transfection with siRNA against both ALDOC and ENO2 determined a significant reduction in lactate production and cell viability. Furthermore, both the number and size of spheroids produced by H460, HCC827, MCF7, and T47D cell lines were significantly reduced upon ALDOC and ENO2 knockdown. Conclusions Our results show that anchorage-independent survival and growth of cancer cells are supported by changes in genes and proteins that drive glucose metabolism towards an enhanced lactate production. Notably, this finding is valid regardless of the tumor type and nutrient environmental availability, thus suggesting the possible general involvement of this mechanism in cancer metastasis. The pan-cancer validation of this vulnerability could potentially help to slow or prevent cancer progression.

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Section: Discussionmentioning

confidence: 91%

ALDOC- and ENO2- driven glucose metabolism sustains 3D tumor spheroids growth regardless of nutrient environmental conditions: a multi-omics analysis

Vitis

Battaglia

Pallocca

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Similarly, the activation of the mevalonate pathway, responsible for cholesterol synthesis, confers stem cell traits to breast cancer cells. In agreement, the inhibition of HMG-CoA reductase, the rate-limiting enzyme of the mevalonate cascade, resulted effective against breast cancer stem cells [ 103 ].…”

Section: Discussionmentioning

confidence: 91%

ALDOC- and ENO2- driven glucose metabolism sustains 3D tumor spheroids growth regardless of nutrient environmental conditions: a multi-omics analysis

Vitis

Battaglia

Pallocca³

et al. 2023

J Exp Clin Cancer Res

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Background Metastases are the major cause of cancer-related morbidity and mortality. By the time cancer cells detach from their primary site to eventually spread to distant sites, they need to acquire the ability to survive in non-adherent conditions and to proliferate within a new microenvironment in spite of stressing conditions that may severely constrain the metastatic process. In this study, we gained insight into the molecular mechanisms allowing cancer cells to survive and proliferate in an anchorage-independent manner, regardless of both tumor-intrinsic variables and nutrient culture conditions. Methods 3D spheroids derived from lung adenocarcinoma (LUAD) and breast cancer cells were cultured in either nutrient-rich or -restricted culture conditions. A multi-omics approach, including transcriptomics, proteomics, and metabolomics, was used to explore the molecular changes underlying the transition from 2 to 3D cultures. Small interfering RNA-mediated loss of function assays were used to validate the role of the identified differentially expressed genes and proteins in H460 and HCC827 LUAD as well as in MCF7 and T47D breast cancer cell lines. Results We found that the transition from 2 to 3D cultures of H460 and MCF7 cells is associated with significant changes in the expression of genes and proteins involved in metabolic reprogramming. In particular, we observed that 3D tumor spheroid growth implies the overexpression of ALDOC and ENO2 glycolytic enzymes concomitant with the enhanced consumption of glucose and fructose and the enhanced production of lactate. Transfection with siRNA against both ALDOC and ENO2 determined a significant reduction in lactate production, viability and size of 3D tumor spheroids produced by H460, HCC827, MCF7, and T47D cell lines. Conclusions Our results show that anchorage-independent survival and growth of cancer cells are supported by changes in genes and proteins that drive glucose metabolism towards an enhanced lactate production. Notably, this finding is valid for all lung and breast cancer cell lines we have analyzed in different nutrient environmental conditions. broader Validation of this mechanism in other cancer cells of different origin will be necessary to broaden the role of ALDOC and ENO2 to other tumor types. Future in vivo studies will be necessary to assess the role of ALDOC and ENO2 in cancer metastasis.

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“…Targeting cancer energy metabolism, including the regulation of glucose and lipids, has emerged as a promising therapeutic approach 70,71 . The "Warburg effect," also known as aerobic glycolysis, which was discovered in the last century, provides signi cant evidence of reprogrammed energy metabolism in cancer cells 72,73,74 .…”

Section: Discussionmentioning

confidence: 99%

HN1-mediated Activation of Lipogenesis Through AKT-SREBP Signaling Promotes Hepatocellular Carcinoma Cell Proliferation and Metastasis

Kim,

Jin,

Meng

et al. 2024

Preprint

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Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide, with more than 800,000 deaths each year, and its five-year survival rate is less than 12%. The role of the HN1 gene in HCC has remained elusive, despite its upregulation in various cancer types. In our investigation, we identified HN1’s heightened expression in HCC tissues, which, upon overexpression, fosters cell proliferation, migration, and invasion, unveiling its role as an oncogene in HCC. In addition, silencing HN1 diminished the viability and metastasis of HCC cells, whereas HN1 overexpression stimulated their growth and invasion. Gene expression profiling revealed HN1 silencing downregulated 379 genes and upregulated 130 genes, and suppressive proteins associated with the lipogenic signaling pathway networks. Notably, suppressing HN1 markedly decreased the expression levels of SREBP1 and SREBP2, whereas elevating HN1 had the converse effect. This dual modulation of HN1 affected lipid formation, hindering it upon HN1 silencing and promoting it upon HN1 overexpression. Moreover, HN1 triggers the Akt pathway, fostering tumorigenesis via SREBP1-mediated lipogenesis and silencing HN1 effectively curbed HCC tumor growth in mouse xenograft models by deactivating SREBP-1, emphasizing the potential of HN1 as a therapeutic target, impacting both external and internal factors, it holds promise as an effective therapeutic strategy for HCC.

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Targeting Energy Metabolism in Cancer Treatment

Cited by 16 publications

References 402 publications

ALDOC- and ENO2- driven glucose metabolism sustains 3D tumor spheroids growth regardless of nutrient environmental conditions: a multi-omics analysis

ALDOC- and ENO2- driven glucose metabolism sustains 3D tumor spheroids growth regardless of nutrient environmental conditions: a multi-omics analysis

ALDOC- and ENO2- driven glucose metabolism sustains 3D tumor spheroids growth regardless of nutrient environmental conditions: a multi-omics analysis

HN1-mediated Activation of Lipogenesis Through AKT-SREBP Signaling Promotes Hepatocellular Carcinoma Cell Proliferation and Metastasis

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