mitochondrial mutations | Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Posts Tagged ‘mitochondrial mutations’

Warburg Effect Revisited

Posted in Anaerobic Glycolysis, Cachexia, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Genomic Expression, Hexokinase, Metabolomics, Methylation, mtDNA, Oxidative phosphorylation, Personalized and Precision Medicine & Genomic Research, Proteomics, Pyruvate Kinase, Warburg effect, tagged cancer biology, carcinogenesis, FLIP expression, Glycolysis, HIF1a, Kras/LKB1 tumors, mitochondrial complex I, mitochondrial function, mitochondrial mutations, mtDNA, NSCLC subtype, PIM2, PIM2-dependent phosphorylation of PKM2, PKM2, Pyruvate Kinase, Warburg Effect on November 28, 2013| Leave a Comment »

Warburg Effect Revisited

Reporter: Larry H. Bernstein, MD, FCAP

We have previously covered the Warburg Effect, and there has been a number of comments about the chicken or the egg! There is an underlying factor that makes it difficult to comprehend that the initiation of cancer is mutation driven, although we are clear that smoking and a number of environmental factors are instigators of the change. The main problem that I have referred to is the chemical, thermodynamic, and evolutionary state of our existence. I strongly refer to the work of Ilya Prigogene. There is a progressive series of changes over time, and it is not possible to determine the initial state. Consequently, a progressive series of adaptations progresses, involving gene expression, non-genetic changes, and metabolic equilibrium that is maintained, but becomes non-adaptive.

Previous discussions at LPI are:

AMPK Is a Negative Regulator of the Warburg Effect and Suppresses Tumor Growth In Vivo
Reporter-Curator: Stephen J. Williams, Ph.D.
http://pharmaceuticalintelligence.com/2013/03/12/ampk-is-a-negative-regulator-of-the-warburg-effect-and-suppresses-tumor-growth-in-vivo/

Is the Warburg Effect the Cause or the Effect of Cancer: A 21st Century View?
Author: Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2012/10/17/is-the-warburg-effect-the-cause-or-the-effect-of-cancer-a-21st-century-view/

Otto Warburg, A Giant of Modern Cellular Biology
Reporter: Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2012/11/02/otto-warburg-a-giant-of-modern-cellular-biology/

Targeting Mitochondrial-bound Hexokinase for Cancer Therapy
Author: Ziv Raviv, PhD
http://pharmaceuticalintelligence.com/2013/04/06/targeting-mito…cancer-therapy

Portrait of a great scientist and mentor: Nathan Oram Kaplan
Writer and Curator, Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2013/01/26/portrait-of-a-great-scientist-and-mentor-nathan-oram-kaplan/

Quantum Biology And Computational Medicine
Author and Curator, Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2013/04/03/quantum-biology-and-computational-medicine/

Ubiquitin-Proteosome pathway, Autophagy, the Mitochondrion, Proteolysis and Cell Apoptosis: Part III
Curator: Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2013/02/14/ubiquinin-proteosome-pathway-autophagy-the-mitochondrion-proteolysis-and-cell-apoptosis-reconsidered/

Differentiation Therapy – Epigenetics Tackles Solid Tumors
Author-Writer: Stephen J. Williams, Ph.D.
http://pharmaceuticalintelligence.com/2013/01/03/differentiation-therapy-epigenetics-tackles-solid-tumors/

Prostate Cancer Cells: Histone Deacetylase Inhibitors Induce Epithelial-to-Mesenchymal Transition
Reporter-Curator: Stephen J. Williams, Ph.D.
http://pharmaceuticalintelligence.com/2012/11/30/histone-deacetylase-inhibitors-induce-epithelial-to-mesenchymal-transition-in-prostate-cancer-cells/

Mitochondrial Damage and Repair under Oxidative Stress
Curator: Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2012/10/28/mitochondrial-damage-and-repair-under-oxidative-stress/

Mitochondria: Origin from oxygen free environment, role in aerobic glycolysis, metabolic adaptation
Curator: Larry H Bernsatein, MD, FCAP
http://pharmaceuticalintelligence.com/2012/09/26/mitochondria-origin-from-oxygen-free-environment-role-in-aerobic-glycolysis-metabolic-adaptation/

Nitric Oxide has a ubiquitous role in the regulation of glycolysis -with a concomitant influence on mitochondrial function
Curator, Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2012/09/16/nitric-oxide-has-a-ubiquitous-role-in-the-regulation-of-glycolysis-with-a-concomitant-influence-on-mitochondrial-function/

Potential Drug Target: Glucolysis Regulation – Oxidative stress-responsive microRNA-320
Reporter: Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2012/07/25/potential-drug-target-glucolysis-regulation-oxidative-stress-responsive-microrna-320/

Expanding the Genetic Alphabet and Linking the Genome to the Metabolome
Reporter& Curator: Larry Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2012/09/24/expanding-the-genetic-alphabet-and-linking-the-genome-to-the-metabolome/

What can we expect of tumor therapeutic response?
Author: Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2012/12/05/what-can-we-expect-of-tumor-therapeutic-response/

A Second Look at the Transthyretin Nutrition Inflammatory Conundrum
Larry H. Bernstein, MD, FACP
http://pharmaceuticalintelligence.com/2012/12/03/a-second-look-at-the-transthyretin-nutrition-inflammatory-conundrum/

Radoslav Bozov
Date: 3/26/2013
Subject: RE: comment
The process of genomic evolution cannot be revealed throughout comparative genomics as structural data representation does not illuminate either the integral path of particles-light interference, as Richard Feynman suggests, in stable forms of matter such as interference/entanglement of the nature of particles/strings/waves to first approximation as I have claimed. Towards the compressibility principle realization, I have claimed that DNA would be entropic- favorable stable state going towards absolute ZERO temp in the space defined itself. In other words themodynamics measurement in subnano discrete space would go negative towards negativity. DNA is sort of like a cold melting/growing crystal, quite stable as it appears not due to hydrogen bonding , but due to interference of C-N-O. That force is contradicted via proteins onto which we now know large amount of negative quantum redox state carbon attaches. Chemistry is just a language as it is math following certain rules based on observation. Most stable states are most observed ones. The more locally one attempts to observe, the more hidden variables would emerge as a consequence of discrete energy spaces opposing continuity of matter/time. Still, stability emerges out of non stability states. And if life was in absolute stability, there will be neither feelings nor freedom. What is feelings and freedom is a far reaching philosophical question with sets of implications, to one may be a driving car, to another riding a horse or a bicycle etc cetera or simply seeing the unobservable …No wonder genome size differs among organisms and even tissue types as an outcome of carbon capacity.

PIM2 phosphorylates PKM2 and promotes Glycolysis in Cancer Cells

Yu Z, Huang L, Zhang T, Yang F, Xie L, Liu J, Song S, Miao P, Zhao L, Zhao X, Huang G.
Shanghai Jiao Tong University, China;
J Biol Chem. 2013 Oct 18. [Epub ahead of print]

Pyruvate kinase M2 (PKM2) is a key player in the Warburg effect of cancer cells.
the mechanisms of regulating PKM2 are not fully elucidated.
we identified the serine/threonine protein kinase PIM2, a known oncogene,
- as a novel binding partner of PKM2.

The interaction between PIM2 and PKM2 was confirmed by multiple biochemical approaches in vitro and in cultured cells. Importantly, we found that

PIM2 could directly phosphorylate PKM2 on the Thr454 residue, resulting in
- an increase of PKM2 protein levels.

Compared to wild-type, PKM2 with the phosphorylation-defective mutation

displayed a reduced effect on glycolysis, co-activating HIF-1α and β-catenin, and cell proliferation,
while enhanced mitochondria respiration and chemotherapeutic sensitivity of cancer cells.

These findings demonstrate that PIM2-dependent phosphorylation of PKM2 is critical for regulating the Warburg effect in cancer,

highlighting PIM2 as a potential therapeutic target.

KEYWORDS: Cancer, Cell proliferation, Glycolysis, Pyruvate kinase, phosphorylation
PMID: 24142698

Different mtDNA mutations modify tumor progression in dependence of the degree of respiratory complex I impairment.

Iommarini L, Kurelac I, Capristo M, Calvaruso MA, Giorgio V, Bergamini C, Ghelli A, et al.
Dipartimento di Farmacia e Biotecnologie (FABIT).
Hum Mol Genet. 2013 Nov 11. [Epub ahead of print]

Mitochondrial DNA mutations are currently investigated as modifying factors impinging on tumor growth and aggressiveness,

having been found in virtually all cancer types and
most commonly affecting genes encoding mitochondrial complex I (CI) subunits.

It is still unclear whether they exert a pro- or anti-tumorigenic effect.

We here analyzed the impact of three homoplasmic mtDNA mutations (m.3460G>A/MT-ND1, m.3571insC/MT-ND1 and m.3243A>G/MT-TL1) on osteosarcoma progression,

chosen since they induce different degrees of oxidative phosphorylation impairment.

In fact, the m.3460G>A/MT-ND1 mutation caused only a reduction in CI activity, whereas

the m.3571insC/MT-ND1 and the m.3243A>G/MT-TL1 mutations induced a severe structural and functional CI alteration.

As a consequence, this severe CI dysfunction determined an energetic defect associated with a compensatory increase in glycolytic metabolism and AMP-activated protein kinase activation.

Osteosarcoma cells carrying such marked CI impairment

displayed a reduced tumorigenic potential both in vitro and in vivo, when compared with cells with mild CI dysfunction, suggesting that
mtDNA mutations may display diverse impact on tumorigenic potential depending on
the type and severity of the resulting oxidative phosphorylation dysfunction.

The modulation of tumor growth was independent from reactive oxygen species production but correlated with

hypoxia-inducible factor 1α stabilization, indicating that
structural and functional integrity of CI and oxidative phosphorylation are required for hypoxic adaptation and tumor progression.

PMID: 24163135 [PubMed – as supplied by publisher]

Systematic Identification of Molecular Subtype-Selective Vulnerabilities in Non-Small-Cell Lung Cancer

Hyun Seok Kim, Saurabh Mendiratta, Jiyeon Kim, Chad Victor Pecot, Jill E. Larsen, et al.
Cell, 24 Oct 2013; 155 (3): 552-566, doi:10.1016/j.cell.2013.09.041
Systematic isolation of context-dependent vulnerabilities in NSCLC

Highlights

NLRP3 mutations drive addiction to FLIP expression
Lysosome maturation is a metabolic bottleneck for KRAS/LKB1 tumors
Selective sensitivity to an indolotriazine discriminates a NSCLC expression subtype