Mitochondrial DNA and Cancer

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Mitochondrial DNA and Cancer

• Steven Sorscher

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Background

• Mechanisms of oncogenesis are generally thought
  to involve nuclear DNA
• Gain of oncogene function
• Loss of tumor suppressor gene function

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Background

• Do somatic mutations in mitochondria DNA (mtDNA)
  contribute to oncogenesis or progression of
  cancer?
• Do nuclear mutations effect mitochondrial
  function and contribute to oncogenesis or
  progression of cancer?

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Pasteur

• Mitochondrial Oxidative phosphorylation
  (OXPHOS) produces ATP and Reactive Oxygen Species
  (ROS) and is more efficient in producing ATP than
  glycolysis occurring in the cytosol. However,
  with low O2, there is a shift to glycolysis
  (Pasteur effect)

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Pasteur

• Fortune favors the prepared mind
• "Gentlemen, you bring me the greatest happiness
  that can be experienced by a man whose invincible
  belief is that science and peace will triumph
  over ignorance and war. Have faith that in the
  long run the future will belong not to the
  conquerors but to the saviors of mankind.
• "One must work one must work. I have done what I
  could.
• Hydrophobia

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Otto Warburg

• "Cancer does not appear by accident, and
  consequently, I would not eat anything treated
  with chemicals in any way, that's why I mainly
  eat what we grow in our own organic garden.
• When frustrated by the lack of acceptance of his
  ideas, Warburg was known to quote an aphorism he
  attributed to Max Planck that science doesn't
  progress because scientists change their minds,
  but rather because scientists attached to
  erroneous views die, and are replaced

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Otto Warburg, Nobel Prize, 1931

• Cancer, above all other diseases, has countless
  secondary causes. But, even for cancer, there is
  only one prime cause. Summarized in a few words,
  the prime cause of cancer is the replacement of
  the respiration of oxygen in normal body cells by
  a fermentation of sugar. Dr. Otto H. Warburg
  in Lecture

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• This originally mysterious phenomenon has been
  explainedthe respiratory grana are autonomous
  organismsthe respiration connected with the
  grana remains damaged when it has once been
  damaged it is for the same reason that properties
  linked with genes remain damaged when genes have
  been damaged Warburg, 1956.
• (ie granamitochondria)

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Background-Mitochondria

• Otto Warburg established that cancer cells favor
  glycolysis over oxygen dependent ATP production,
  even when O2 is present
• Normal cells more heavily rely on OXPHOS or O2
  dependent ATP production
• Whether this is a result of cancer, causes cancer
  or causes cancer progression is incompletely
  understood.
• Understanding mitochondrial abnormalities will
  contribute to that understanding
• Practical Implication of Warburgs discovery

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Pet Scan

• A consequence of understanding the increased
  glycolysis (and therefore increased glucose
  uptake) has led to PET scanning

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• Mitochondrial DNA mutations/expression influence
  nuclear DNA mutations/expression altering
  phenotype
• Nuclear DNA mutations/expression influences
  mitochondrial DNA mutation/expression altering
  phenotype

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Mitochondria Influences

• mtDNA is frequently mutated in both normal and
  cancer cells
• Explanations in normal cells
• Poorer fidelity of DNA replicating enzyme
  polymerase gamma
• Reactive O2 species cause more mtDNA damage
• No mtDNA repair mechanisms in place

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Mitochondria

• Normal and cancer cells both harbor mutated
  mtDNA, although mt mutations are much more common
  in cancer cells
• gt50 of cancer cells show functionally relevant
  point mutations (Linnartz)
• Computer modeling suggests this difference could
  be due to proliferation in cancer and selection
  for physiologic advantage (Coller)

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Mitochondriia

• Regardless
• mtDNA mutations are more common in cancer
  (guilt by association)

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Mutated mtDNA in cancer

• PCR followed by manual sequencing of mtDNA in
  tumor vs paired blood samples and normal tissue
• Acquired mutations were seen
• 64 of bladder cancers, 46 of head and neck
  cancers and 43 of lung cancer cases (Fliss)

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Mutated mtDNA in Cancer

• Breast cancer In 11 of 18 primary breast
  cancers, 12 somatic mutations were seen that were
  not seen in matched lymphocytes and normal breast
  tissue (61)
• 
  (Parrella)

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Mitochondria Function and effect on Nuclear genes

• Depletion of mt genome leads to chromosomal
  instability seen in a variety of tumors
• Cells with depleted mitochondria undergo
  transformation
• Specific DNA repair and transcription proteins
  (eg APE1) are altered in mt depleted cells and
  the transformed phenotype can be reversed by
  introducing WT mt.
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  (Amuthan)

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Cancer Phenotype Induction (Shidara)

• Mutated mtDNA coding for an ATP synthase subunit
  was introduced into HeLa cells devoid of mtDNA
  producing trans-mitochondrial hybrids (cybrids)
• The cybrids with mutated mtDNA showed a tumor
  growth advantage in nude mice and prevented
  apoptosis
• Transfection of the corresponding WTmtDNA slowed
  the growth

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Cancer Phenotype Induction

• Cybrids expressing the mutated mtDNA also showed
  reduced OXPHOS (favored glycolysis)
• Conclusion
• mutated mtDNA prevents apoptosis

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Nuclear DNA products acting in the
Mitochondria

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Effects of Nuclear DNA on Mitochondrial Function

• Germline mutations in nuclear DNA (whose products
  are mt acting)
• Mt succinate dehydrogenase (SDH) causes
  inherited pheochromocytomas and paragangliomas
• Fumarate hydratase (FH) causes inherited
  leiomyomas and RCCs
• (apparently due to increased HIF expression with
  SDH or FH loss)

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Effects of nuclear DNA on Mitochondrial function
(Vecchione)

• LOH in 12q24 seen in multiple cancer (breast,
  lung, prostate, pancreas,renal)
• Mitostatin-putative tumor suppressor
  gene-recently cloned from this region. Deleted or
  mutated in 5-11 of cancers or cell lines
  screened (particularly bladder and breast)
• Introduction and expression of WT Mitostatin is
  proapoptotic .

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Mitostatin

• Cells lacking WT Mitostatin cells showed an
  increase cell growth and cell survival
• Heat shock protein (HSP)27 has been correlated
  with increased metastases and resistance to
  therapy (Kamada) through mitochondrial effects
• WT Mitostatin appears to downregulate
  activated heat shock protein HSP27. Therefore
  loss of WT Mitostatin induces Hsp27 and promotes
  metastases and resistance, apparently by
  mitochondrial effects.

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Cancer Phenotype Induction (Petros)

• Mutations in certain nuclear genes (eg succinate
  dehydrogene C involved in OXPHOS) markedly
  increases ROS production which appears to
  inactivate p53 and cause additional mtDNA
  mutations
• Also, SDH deficiency leads to succinate
  accumulation in the cytosol where it inhibits
  prolyl hydroxylases and thereby HIF-1alpha
  degradation. Increased HIF 1-alpha results in
  nuclear gene expression causing tumor progression
  (Selak)

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Conclusions

• Cancer relies relatively more on glycolysis
  (Warburg) and mutated mtDNA is more common in
  cancer
• Nuclear/Mitochondrial crosstalk appears to
  contribute to oncogenesis/tumor progression.
  Abnormal mitochondrial functioning due to
  aberrant nuclear proteins or aberrant nuclear
  proteins due to mt DNA mutations induce cancer
  phenotypes
• Although glycolysis characterizes cancer, its
  cause and causal relationship to cancer remains
  unclear (Maximo, 2009)

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Charles Darwin

• "Ignorance more frequently begets confidence than
  does knowledge it is those who know little, not
  those who know much, who so positively assert
  that this or that problem will never be solved by
  science.
• "Man with all his noble qualities, with sympathy
  which feels for the most debased, with
  benevolence which extends not only to other men
  but to the humblest living creature, with his
  god-like intellect which has penetrated into the
  movements and constitution of the solar system-
  with all these exalted powers- Man still bears in
  his bodily frame the indelible stamp of his lowly
  origin."
• "But when on shore, wandering in the sublime
  forests, surrounded by views more gorgeous than
  even Claude ever imagined, I enjoy a delight
  which none but those who have experienced it can
  understand