Succinate Dehydrogenase Loss in Familial Paraganglioma: Biochemistry, Genetics, and Epigenetics

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Abstract

It is counterintuitive that metabolic defects reducing ATP production can cause, rather than protect from, cancer. Yet this is precisely the case for familial paraganglioma, a form of neuroendocrine malignancy caused by loss of succinate dehydrogenase in the tricarboxylic acid cycle. Here we review biochemical, genetic, and epigenetic considerations in succinate dehydrogenase loss and present leading models and mysteries associated with this fascinating and important tumor.

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Most cited references 113

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Akt stimulates aerobic glycolysis in cancer cells.

Rebecca Elstrom, Daniel E Bauer, Monica Buzzai … (2004)

Cancer cells frequently display high rates of aerobic glycolysis in comparison to their nontransformed counterparts, although the molecular basis of this phenomenon remains poorly understood. Constitutive activity of the serine/threonine kinase Akt is a common perturbation observed in malignant cells. Surprisingly, although Akt activity is sufficient to promote leukemogenesis in nontransformed hematopoietic precursors and maintenance of Akt activity was required for rapid disease progression, the expression of activated Akt did not increase the proliferation of the premalignant or malignant cells in culture. However, Akt stimulated glucose consumption in transformed cells without affecting the rate of oxidative phosphorylation. High rates of aerobic glycolysis were also identified in human glioblastoma cells possessing but not those lacking constitutive Akt activity. Akt-expressing cells were more susceptible than control cells to death after glucose withdrawal. These data suggest that activation of the Akt oncogene is sufficient to stimulate the switch to aerobic glycolysis characteristic of cancer cells and that Akt activity renders cancer cells dependent on aerobic glycolysis for continued growth and survival.

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Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma.

B E Baysal, R Ferrell, J Willett-Brozick … (2000)

Hereditary paraganglioma (PGL) is characterized by the development of benign, vascularized tumors in the head and neck. The most common tumor site is the carotid body (CB), a chemoreceptive organ that senses oxygen levels in the blood. Analysis of families carrying the PGL1 gene, described here, revealed germ line mutations in the SDHD gene on chromosome 11q23. SDHD encodes a mitochondrial respiratory chain protein-the small subunit of cytochrome b in succinate-ubiquinone oxidoreductase (cybS). In contrast to expectations based on the inheritance pattern of PGL, the SDHD gene showed no evidence of imprinting. These findings indicate that mitochondria play an important role in the pathogenesis of certain tumors and that cybS plays a role in normal CB physiology.

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Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay.

Tania Fiaschi, Alberto Marini, Elisa Giannoni … (2012)

Cancer-associated fibroblasts (CAF) engage in tumor progression by promoting the ability of cancer cells to undergo epithelial-mesenchymal transition (EMT), and also by enhancing stem cells traits and metastatic dissemination. Here we show that the reciprocal interplay between CAFs and prostate cancer cells goes beyond the engagement of EMT to include mutual metabolic reprogramming. Gene expression analysis of CAFs cultured ex vivo or human prostate fibroblasts obtained from benign prostate hyperplasia revealed that CAFs undergo Warburg metabolism and mitochondrial oxidative stress. This metabolic reprogramming toward a Warburg phenotype occurred as a result of contact with prostate cancer cells. Intercellular contact activated the stromal fibroblasts, triggering increased expression of glucose transporter GLUT1, lactate production, and extrusion of lactate by de novo expressed monocarboxylate transporter-4 (MCT4). Conversely, prostate cancer cells, upon contact with CAFs, were reprogrammed toward aerobic metabolism, with a decrease in GLUT1 expression and an increase in lactate upload via the lactate transporter MCT1. Metabolic reprogramming of both stromal and cancer cells was under strict control of the hypoxia-inducible factor 1 (HIF1), which drove redox- and SIRT3-dependent stabilization of HIF1 in normoxic conditions. Prostate cancer cells gradually became independent of glucose consumption, while developing a dependence on lactate upload to drive anabolic pathways and thereby cell growth. In agreement, pharmacologic inhibition of MCT1-mediated lactate upload dramatically affected prostate cancer cell survival and tumor outgrowth. Hence, cancer cells allocate Warburg metabolism to their corrupted CAFs, exploiting their byproducts to grow in a low glucose environment, symbiotically adapting with stromal cells to glucose availability. ©2012 AACR.

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Author and article information

Journal

Journal ID (nlm-ta): Int J Endocrinol

Journal ID (iso-abbrev): Int J Endocrinol

Journal ID (publisher-id): IJE

Title: International Journal of Endocrinology

Publisher: Hindawi Publishing Corporation

ISSN (Print): 1687-8337

ISSN (Electronic): 1687-8345

Publication date (Print): 2015

Publication date (Electronic): 29 July 2015

Volume: 2015

Electronic Location Identifier: 296167

Affiliations

¹Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA

²Mayo Clinic Medical Scientist Training Program, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA

Author notes

*L. James Maher III: maher@ 123456mayo.edu

Academic Editor: Mario Maggi

Article

DOI: 10.1155/2015/296167

PMC ID: 4532907

PubMed ID: 26294907

SO-VID: ae161e7d-9990-4d98-8a30-153c493d9a05

License:

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 1 June 2015

Date accepted : 5 July 2015

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Succinate Dehydrogenase Loss in Familial Paraganglioma: Biochemistry, Genetics, and Epigenetics

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Abstract

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Journal of the ASEAN Federation of Endocrine Societies

Most cited references 113

Akt stimulates aerobic glycolysis in cancer cells.

Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma.

Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay.

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Cited by 19

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