Dataset Information

MYC Expression and Metabolic Redox Changes in Cancer Cells: A Synergy Able to Induce Chemoresistance.

ABSTRACT: Chemoresistance is due to multiple factors including the induction of a metabolic adaptation of tumor cells. In fact, in these cells, stress conditions induced by therapies stimulate a metabolic reprogramming which involves the strengthening of various pathways such as glycolysis, glutaminolysis and the pentose phosphate pathway. This metabolic reprogramming is the result of a complex network of mechanisms that, through the activation of oncogenes (i.e., MYC, HIF1, and PI3K) or the downregulation of tumor suppressors (i.e., TP53), induces an increased expression of glucose and/or glutamine transporters and of glycolytic enzymes. Therefore, in order to overcome chemoresistance, it is necessary to develop combined therapies which are able to selectively and simultaneously act on the multiple molecular targets responsible for this adaptation. This review is focused on highlighting the role of MYC in modulating the epigenetic redox changes which are crucial in the acquisition of therapy resistance.

SUBMITTER: Marengo B

PROVIDER: S-EPMC6614970 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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MYC Expression and Metabolic Redox Changes in Cancer Cells: A Synergy Able to Induce Chemoresistance.

Marengo Barbara B Garbarino Ombretta O Speciale Andrea A Monteleone Lorenzo L Traverso Nicola N Domenicotti Cinzia C

Oxidative medicine and cellular longevity 20190625

Chemoresistance is due to multiple factors including the induction of a metabolic adaptation of tumor cells. In fact, in these cells, stress conditions induced by therapies stimulate a metabolic reprogramming which involves the strengthening of various pathways such as glycolysis, glutaminolysis and the pentose phosphate pathway. This metabolic reprogramming is the result of a complex network of mechanisms that, through the activation of oncogenes (i.e., MYC, HIF1, and PI3K) or the downregulatio ...[more]

PMID: 31341534

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Project description:Inducing ferroptosis in tumor cells is emerging as a strategy for treating malignancies that are refractory to traditional treatment modalities. However, the consequences of ferroptosis of immune cells in the tumor microenvironment need to be better understood in order to realize the potential of this approach. In this study, we discovered that neutrophils in chemoresistant breast cancer are highly sensitive to ferroptosis. Reduction of the acyltransferase MOAT1 in chemoresistance-associated neutrophils induced phospholipid reprogramming, switching the preference from monounsaturated fatty acids to polyunsaturated fatty acids, which increased their susceptibility to ferroptosis. Ferroptotic neutrophils secreted PGE2, IDO, and oxidized lipids that suppressed the proliferation and cytotoxicity of antitumor CD8+ T cells. Furthermore, neutrophil ferroptosis was closely related to a distinct subset of IL1β+CXCL3+CD4+ (Fer-CD4) T lymphocytes, which were enriched in chemoresistant tumors. Fer-CD4 T cells orchestrated neutrophil ferroptosis by modulating MOAT1 expression via IL1β/IL1R1/NF-κB signaling. Moreover, Fer-CD4 T cells secreted CXCL3, IL8, and S100A9 to replenish the neutrophil pool in the tumor microenvironment. Ferroptotic neutrophils in turn fostered Fer-CD4 T-cell differentiation. In spontaneous tumorigenesis mouse models, targeting IL1β+ CD4+ T cells or IL1R1+ neutrophils broke the cross-talk, restraining neutrophil ferroptosis, enhancing antitumor immunity, and overcoming chemoresistance. Overall, these findings uncover the role of neutrophil ferroptosis in shaping the immune landscape and propose appealing targets for restoring immunosurveillance and chemosensitivity in breast cancer. Significance: In chemoresistant breast cancer, IL1β+CXCL3+CD4+ T cells mediate neutrophil ferroptosis that suppresses antitumor immunity, indicating that interfering with this intercellular cross-talk could be an attractive strategy to reverse chemoresistance.

Project description:BackgroundColorectal cancer (CRC) is the third major cause of cancer-related death worldwide, and fluorouracil (5-FU) is widely used in the treatment of CRC. However, acquired resistance to 5-FU has become an obstacle in the effective treatment of CRC. Adenosine triphosphate (ATP)-binding cassette sub-family G member 2 (ABCG2) has been found highly expressed in CRC patients with poor responsiveness to folinic acid/5-FU/irinotecan. However, the mechanisms of 5-FU resistance regulated by ABCG2 in CRC cells remain to be comprehensively understood. We aimed to explore the upstream mechanisms of ABCG2 involved in the regulation of chemoresistance in CRC cells.MethodsWe investigated the potential mechanisms of 5-FU resistance in HCT116, RKO, RKO microRNA-21 (miR-21) knockout, and acquired 5-FU-resistant HCT116 (HCT116/FUR) cells. The biochemical and biological analyses were conducted using semiquantitative reverse transcription-polymerase chain reaction (qRT-PCR), western blotting, transfections, and rescue experiments, along with cell proliferation, viability, and colony formation assays. In order to investigate the efficacy of inhibiting the c-Jun NH2 terminal kinase (JNK) pathway to overcome 5-FU resistance, HCT116 and 5-FU-resistant HCT116 cells were inoculated into BALB/c-nu/nu mice to establish the cell-derived xenograft model.ResultsThe results showed that ABCG2 expression in HCT116/FUR cells was higher compared to HCT116 cells. Overexpression of ABCG2 decreased sensitivity to 5-FU in HCT116 cells, but knockdown of ABCG2 decreased the survival rate in HCT116/FUR cells. Additionally, repressing programmed cell death 4 (PDCD4) activated the JNK pathway in HCT116/FUR cells. Overexpression of PDCD4 inhibited phosphorylation of c-Jun and ABCG2 expression, and recovered sensitivity to 5-FU in HCT116/FUR cells. Moreover, treatment with the JNK pathway inhibitor SP600125 downregulated ABCG2 expression and rescued sensitivity to 5-FU in HCT116/FUR cells. We also found that miR-21 expression in HCT116/FUR cells was higher compared to HCT116 cells. Finally, 5-FU treatment in combination with SP600125 significantly decreased tumorigenicity compared to other treatments in vivo.ConclusionsOur results demonstrated that 5-FU treatment upregulated miR-21, which directly repressed PDCD4, and subsequently activated the JNK pathway, leading to the upregulation of ABCG2 in CRC cells. Inhibition of the JNK pathway overcame acquired 5-FU resistance both in vivo and in vitro.

Dataset Information

MYC Expression and Metabolic Redox Changes in Cancer Cells: A Synergy Able to Induce Chemoresistance.

Publications

MYC Expression and Metabolic Redox Changes in Cancer Cells: A Synergy Able to Induce Chemoresistance.

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