Rescue of TCA Cycle Dysfunction for Cancer Therapy

Marquez, Jubert; Flores, Josean; Ah, Kim Jong; Nyamaa, Bayalagmaa; Att, Nguyen; Park, N; Han, Jin

doi:10.3390/jcm8122161

Cited by 35 publications

(23 citation statements)

References 128 publications

(132 reference statements)

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“…Mutations of a single arginine in the catalytic site of IDH1 and IDH2 were observed in several malignancies, including glioblastoma, acute myeloid leukemia (AML) and cholangiocarcinoma, leading to a gain-of-function. The mutated IDH catalyzes the conversion of αKG to the tumor-specific metabolite 2-hydroxyglutarate (2-HG), which induces cellular proliferation by activating the mTOR-signaling pathway and inhibiting αKG-dependent dioxygenases that are involved in the regulation of epigenetics and differentiation in vitro [ 116 , 128 , 129 ].…”

Section: Mitochondrial Metabolism Of Colorectal Cancermentioning

confidence: 99%

Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities

Neitzel

Demuth

Wittmann

et al. 2020

Cancers

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Colorectal cancer (CRC) is among the most frequent cancer entities worldwide. Multiple factors are causally associated with CRC development, such as genetic and epigenetic alterations, inflammatory bowel disease, lifestyle and dietary factors. During malignant transformation, the cellular energy metabolism is reprogrammed in order to promote cancer cell growth and proliferation. In this review, we first describe the main alterations of the energy metabolism found in CRC, revealing the critical impact of oncogenic signaling and driver mutations in key metabolic enzymes. Then, the central role of mitochondria and the tricarboxylic acid (TCA) cycle in this process is highlighted, also considering the metabolic crosstalk between tumor and stromal cells in the tumor microenvironment. The identified cancer-specific metabolic transformations provided new therapeutic targets for the development of small molecule inhibitors. Promising agents are in clinical trials and are directed against enzymes of the TCA cycle, including isocitrate dehydrogenase, pyruvate dehydrogenase kinase, pyruvate dehydrogenase complex (PDC) and α-ketoglutarate dehydrogenase (KGDH). Finally, we focus on the α-lipoic acid derivative CPI-613, an inhibitor of both PDC and KGDH, and delineate its anti-tumor effects for targeted therapy.

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Section: Mitochondrial Metabolism Of Colorectal Cancermentioning

confidence: 99%

Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities

Neitzel

Demuth

Wittmann

et al. 2020

Cancers

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“…To date, LDH is an enzyme that catalyzes the pyruvate to lactate during anaerobic conditions. The metabolomic pro le of cancer patients is well-described as altered in that to promote the accumulation of pyruvate which leads to both the anaerobic (LDH-dependent) and tricyclic acid (TCA) pathway according to the tumor cell metabolic needs (30,31). Therefore, tumor-associated as well as circulating (12) caspase-4 suggest that the in ammatory pattern in tumor cells alters the metabolomic pro le to favor cell proliferation rather than cell death.…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel subpopulation of Caspase-4 positive Non-Small Cell Lung Cancer patients.

Terlizzi

Colarusso

Rosa³

et al. 2020

Preprint

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Background . Therapy/prognosis of Non-Small Cell Lung Cancer (NSCLC) patients are strongly related to gene alteration/s or protein expression. However, more than 50% of NSCLC patients are negative to key drugable biomarkers. Methods: We used human samples of NSCLC and mouse models of lung adenocarcinoma. Results . We showed that caspase-4 was highly present in the tumor mass compared to non-cancerous human tissues. Interestingly, the orthologue murine caspase-11 promoted lung carcinogenesis in mice. Carcinogen-exposed caspase-11 knockout mice had lower tumor lesions than wild type mice, due to the relevance of caspase-11 in the structural lung cell as demonstrated by bone marrow transplantation and adoptive transfer experiments. Similarly to what observed in mice, caspase-4 was correlated to the stage of lung cancer in humans in that it induced cell proliferation in a K-Ras, c-MyC and IL-1α dependent manner. Caspase-4 positive adenocarcinoma (79,3%) and squamous carcinoma (88.2%) patients had lower median survival than patients who had lower levels of caspase-4. Moreover, PD-L1 expression and gene mutation (i.e. EGFR) were not correlated to caspase-4 expression. Instead, NSCLC patients who had K-Ras or c-MyC gene alteration were positively correlated to higher levels of caspase-4 and lower survival rate. Conclusions . We identified a subgroup of NSCLC patients as caspase-4 positive among which double and triple positive caspase-4, K-Ras and/or c-MyC patients which prognosis was poor. Because K-Ras and c-MyC are still undrugable, the identification of caspase-4 as a novel oncoprotein could introduce novelty in the clinical yet unmet needs for NSCLC patients.

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“…To date, LDH is an enzyme that catalyzes the pyruvate to lactate during anaerobic conditions. The metabolomic pro le of cancer patients is well-described as altered in that to promote the accumulation of pyruvate which leads to both the anaerobic (LDH-dependent) and tricyclic acid (TCA) pathway according to the tumor cell metabolic needs (31,32). Therefore, tumor-associated as well as circulating caspase-4 (12) suggest that the in ammatory pattern in tumor cells alters the metabolomic pro le to favor cell proliferation rather than cell death, as we recently demonstrated (30).…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel subpopulation of Caspase-4 positive Non-Small Cell Lung Cancer patients.

Terlizzi

Colarusso

Rosa³

et al. 2020

Preprint

View full text Add to dashboard Cite

Background. Therapy/prognosis of Non-Small Cell Lung Cancer (NSCLC) patients are strongly related to gene alteration/s or protein expression. However, more than 50% of NSCLC patients are negative to key drugable biomarkers.Methods: We used human samples of NSCLC and mouse models of lung adenocarcinoma. Results. We showed that caspase-4 was highly present in the tumor mass compared to non-cancerous human tissues. Interestingly, the orthologue murine caspase-11 promoted lung carcinogenesis in mice. Carcinogen-exposed caspase-11 knockout mice had lower tumor lesions than wild type mice, due to the relevance of caspase-11 in the structural lung cell as demonstrated by bone marrow transplantation and adoptive transfer experiments. Similarly to what observed in mice, caspase-4 was correlated to the stage of lung cancer in humans in that it induced cell proliferation in a K-Ras, c-MyC and IL-1α dependent manner. Caspase-4 positive adenocarcinoma (79.3%) and squamous carcinoma (88.2%) patients had lower median survival than patients who had lower levels of caspase-4. Moreover, PD-L1 expression and gene mutation (i.e. EGFR) were not correlated to caspase-4 expression. Instead, NSCLC patients who had K-Ras or c-MyC gene alteration were positively correlated to higher levels of caspase-4 and lower survival rate. Conclusions. We identified a subgroup of NSCLC patients as caspase-4 positive among which double and triple positive caspase-4, K-Ras and/or c-MyC patients which prognosis was poor. Because K-Ras and c-MyC are still undrugable, the identification of caspase-4 as a novel oncoprotein could introduce novelty in the clinical yet unmet needs for NSCLC patients.

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Rescue of TCA Cycle Dysfunction for Cancer Therapy

Cited by 35 publications

References 128 publications

Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities

Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities

Identification of a novel subpopulation of Caspase-4 positive Non-Small Cell Lung Cancer patients.

Identification of a novel subpopulation of Caspase-4 positive Non-Small Cell Lung Cancer patients.

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