Regulation of Cancer Metabolism by Oncogenes and Tumor Suppressors

Iurlaro, Raffaella; León-Annicchiarico, Clara Lucía; Muñoz-Pinedo, Cristina

doi:10.1016/b978-0-12-416618-9.00003-0

Cited by 97 publications

(63 citation statements)

References 114 publications

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“…HIFs also operate in conjunction with oncogenic MYC, an oncogene overexpressed in about 30% of human cancers and known to upregulate glycolytic enzymes such as LDH (8). The mTOR pathway is one of the most dysregulated signaling pathways in human cancer, leading to accelerated glucose metabolism by regulating HIF-1α and MYC (9). It was also shown that the BRAF oncogene causes upregulation of genes involved in glycolysis and its knockdown results in reduced glycolysis (10).…”

Section: Tumor Metabolismmentioning

confidence: 99%

Metabolic Hallmarks of Tumor and Immune Cells in the Tumor Microenvironment

et al. 2017

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Cytotoxic T lymphocytes and NK cells play an important role in eliminating malignant tumor cells and the number and activity of tumor-infiltrating T cells represent a good marker for tumor prognosis. Based on these findings, immunotherapy, e.g., checkpoint blockade, has received considerable attention during the last couple of years. However, for the majority of patients, immune control of their tumors is gray theory as malignant cells use effective mechanisms to outsmart the immune system. Increasing evidence suggests that changes in tumor metabolism not only ensure an effective energy supply and generation of building blocks for tumor growth but also contribute to inhibition of the antitumor response. Immunosuppression in the tumor microenvironment is often based on the mutual metabolic requirements of immune cells and tumor cells. Cytotoxic T and NK cell activation leads to an increased demand for glucose and amino acids, a well-known feature shown by tumor cells. These close metabolic interdependencies result in metabolic competition, limiting the proliferation, and effector functions of tumor-specific immune cells. Moreover, not only nutrient restriction but also tumor-driven shifts in metabolite abundance and accumulation of metabolic waste products (e.g., lactate) lead to local immunosuppression, thereby facilitating tumor progression and metastasis. In this review, we describe the metabolic interplay between immune cells and tumor cells and discuss tumor cell metabolism as a target structure for cancer therapy. Metabolic (re)education of tumor cells is not only an approach to kill tumor cells directly but could overcome metabolic immunosuppression in the tumor microenvironment and thereby facilitate immunotherapy.

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Section: Tumor Metabolismmentioning

confidence: 99%

Metabolic Hallmarks of Tumor and Immune Cells in the Tumor Microenvironment

et al. 2017

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“…For example, the tumor suppressor protein p53 which plays a pivotal role in the cellular responses to hypoxia, DNA damage and oncogene activation is now known to regulate glycolysis and assist in maintaining mitochondrial integrity (Olovnikov et al, 2009; Madan et al, 2011; Puzio-Kuter, 2011; Kim and Kim, 2013; Iurlaro et al, 2014; Barron et al, 2016). Another important connection between metabolism and tumor growth is through regulation of c-MYC.…”

Section: Tumor Metabolismmentioning

confidence: 99%

“…Over-activation of the stress responsive PI3K/AKT signaling pathway is typical in many cancers and often due to activation of growth factor signaling pathways involved in glioma growth such as platelet-derived growth factor, epidermal growth factor and insulin growth factor. We now know that these growth factor pathways are intertwined with metabolic signally pathways (Iurlaro et al, 2014; Martini et al, 2014; Courtnay et al, 2015; Dibble and Cantley, 2015; Roberts and Miyamoto, 2015). PI3K/AKT signaling has been closely linked to metabolism and under low glucose conditions results in rapid tumor cell death (Robey and Hay, 2009; Yang et al, 2009; Marie and Shinjo, 2011).…”

Section: Tumor Metabolismmentioning

confidence: 99%

Tumor Metabolism, the Ketogenic Diet and β-Hydroxybutyrate: Novel Approaches to Adjuvant Brain Tumor Therapy

Woolf

Syed

Scheck

2016

Front. Mol. Neurosci.

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Malignant brain tumors are devastating despite aggressive treatments such as surgical resection, chemotherapy and radiation therapy. The average life expectancy of patients with newly diagnosed glioblastoma is approximately ~18 months. It is clear that increased survival of brain tumor patients requires the design of new therapeutic modalities, especially those that enhance currently available treatments and/or limit tumor growth. One novel therapeutic arena is the metabolic dysregulation that results in an increased need for glucose in tumor cells. This phenomenon suggests that a reduction in tumor growth could be achieved by decreasing glucose availability, which can be accomplished through pharmacological means or through the use of a high-fat, low-carbohydrate ketogenic diet (KD). The KD, as the name implies, also provides increased blood ketones to support the energy needs of normal tissues. Preclinical work from a number of laboratories has shown that the KD does indeed reduce tumor growth in vivo. In addition, the KD has been shown to reduce angiogenesis, inflammation, peri-tumoral edema, migration and invasion. Furthermore, this diet can enhance the activity of radiation and chemotherapy in a mouse model of glioma, thus increasing survival. Additional studies in vitro have indicated that increasing ketones such as β-hydroxybutyrate (βHB) in the absence of glucose reduction can also inhibit cell growth and potentiate the effects of chemotherapy and radiation. Thus, while we are only beginning to understand the pluripotent mechanisms through which the KD affects tumor growth and response to conventional therapies, the emerging data provide strong support for the use of a KD in the treatment of malignant gliomas. This has led to a limited number of clinical trials investigating the use of a KD in patients with primary and recurrent glioma.

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“…In particular, cancer cells display glucose avidity and are more sensitive to cell death by starvation than nontransformed cells. This predisposition to cell death has been associated with the hyperactivation of oncogenes and the inactivation of tumor suppressors, most of which regulate glucose uptake and utilization (1–3). …”

Section: Introductionmentioning

confidence: 99%

Glucose Deprivation Induces ATF4-Mediated Apoptosis through TRAIL Death Receptors

Iurlaro

Püschel

León-Annicchiarico

et al. 2017

Molecular and Cellular Biology

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108

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Metabolic stress occurs frequently in tumors and in normal tissues undergoing transient ischemia. Nutrient deprivation triggers, among many potential cell death-inducing pathways, an endoplasmic reticulum (ER) stress response with the induction of the integrated stress response transcription factor ATF4. However, how this results in cell death remains unknown. Here we show that glucose deprivation triggered ER stress and induced the unfolded protein response transcription factors ATF4 and CHOP. This was associated with the nontranscriptional accumulation of TRAIL receptor 1 (TRAIL-R1) (DR4) and with the ATF4-mediated, CHOP-independent induction of TRAIL-R2 (DR5), suggesting that cell death in this context may involve death receptor signaling. Consistent with this, the ablation of TRAIL-R1, TRAIL-R2, FADD, Bid, and caspase-8 attenuated cell death, although the downregulation of TRAIL did not, suggesting ligand-independent activation of TRAIL receptors. These data indicate that stress triggered by glucose deprivation promotes the ATF4-dependent upregulation of TRAIL-R2/DR5 and TRAIL receptor-mediated cell death.

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Regulation of Cancer Metabolism by Oncogenes and Tumor Suppressors

Cited by 97 publications

References 114 publications

Metabolic Hallmarks of Tumor and Immune Cells in the Tumor Microenvironment

Metabolic Hallmarks of Tumor and Immune Cells in the Tumor Microenvironment

Tumor Metabolism, the Ketogenic Diet and β-Hydroxybutyrate: Novel Approaches to Adjuvant Brain Tumor Therapy

Glucose Deprivation Induces ATF4-Mediated Apoptosis through TRAIL Death Receptors

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