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Acquired Mitochondrial Abnormalities, Including Epigenetic Inhibition of Superoxide Dismutase 2, in Pulmonary Hypertension and Cancer: Therapeutic Implications

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Hypoxia

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 903))

Abstract

There is no cure for non-small-cell lung cancer (NSCLC) or pulmonary arterial hypertension (PAH). Therapies lack efficacy and/or are toxic, reflecting a failure to target disease abnormalities that are distinct from processes vital to normal cells. NSCLC and PAH share reversible mitochondrial-metabolic abnormalities which may offer selective therapeutic targets. The following mutually reinforcing, mitochondrial abnormalities favor proliferation, impair apoptosis, and are relatively restricted to PAH and cancer cells: (1) Epigenetic silencing of superoxide dismutase-2 (SOD2) by methylation of CpG islands creates a pseudohypoxic redox environment that causes normoxic activation of hypoxia inducible factor (HIF-1α). (2) HIF-1α increases expression of pyruvate dehydrogenase kinase (PDK), which impairs oxidative metabolism and promotes a glycolytic metabolic state. (3) Mitochondrial fragmentation, partially due to mitofusin-2 downregulation, promotes proliferation. This review focuses on the recent discovery that decreased expression of SOD2, a putative tumor-suppressor gene and the major source of H2O2, results from hypermethylation of CpG islands. In cancer and PAH hypermethylation of a site in the enhancer region of intron 2 inhibits SOD2 transcription. In normal PASMC, SOD2 siRNA decreases H2O2 and activates HIF-1α. In PAH, reduced SOD2 expression decreases H2O2, reduces the cytosol and thereby activates HIF-1α. This causes a glycolytic shift in metabolism and increases the proliferation/apoptosis ratio by downregulating Kv1.5 channels, increasing cytosolic calcium, and inhibiting caspases. The DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine, which restores SOD2 expression, corrects the proliferation/apoptosis imbalance in PAH and cancer cells. The specificity of PAH for lung vessels may relate to the selective upregulation of DNA methyltransferases that mediate CpG methylation in PASMC (DNA MT-1A and -3B). SOD2 augmentation inactivates HIF-1α in PAH PASMC and therapy with the SOD mimetic, MnTBAP, regresses experimental PAH. In conclusion, cancer and PAH share acquired mitochondrial abnormalities that increase proliferation and inhibit apoptosis, suggesting new therapeutic targets.

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Acknowledgements

This paper summarizes original science reported in references [5, 11, 12]. The hypotheses have previously been summarized (in part) in review articles, references [3, 7]. Dr. Archer is supported by NIH-RO1-HL071115 and 1RC1HL099462-01, the American Heart Association (AHA).

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  1. Head Department of Medicine, Queen’s University Program Medical Director KGH, HD, SMOL Etherington Hall, Room 3041 94 Stuart St., Kingston, Ontario, Canada, K7L 3N6

    Stephen L. Archer (Professor)

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  1. Altitude Research Center, University of Colorado Anschutz Medical, AURORA, Colorado, USA

    Robert C. Roach

  2. Institute for Altitude Medicine, Telluride, Colorado, USA

    Peter H. Hackett

  3. Division of Physiology 0623A, University of California - San Diego, La Jolla, California, USA

    Peter D. Wagner

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Archer, S.L. (2016). Acquired Mitochondrial Abnormalities, Including Epigenetic Inhibition of Superoxide Dismutase 2, in Pulmonary Hypertension and Cancer: Therapeutic Implications. In: Roach, R., Hackett, P., Wagner, P. (eds) Hypoxia. Advances in Experimental Medicine and Biology, vol 903. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-7678-9_3

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