Sunday, July 29, 2012

Mitochondrial Dysfunction and Cancer

The Warburg Effect

Cancer is well known for the Warburg effect, which is where tumor cells preferentially convert glucose to lactate, but even in the presence of oxygen (called ‘aerobic glycolysis’).  Even though this produces much less energy, it is advantageous for the tumour cell a number of reasons:

  • It reduces reactive oxygen species (ROS) produced by the tumour cell because a lot of ROS are a by-product of oxidative phosphorylation [1]*
  • It enables tumour cells to not require mitochondria and shut them down, thereby reducing/eliminating pro-apoptosis signalling from mitochondria [1]
  • The intermediary metabolites of glycolysis can be used as substrate for rapid growth [1]
  • Lactate and H+ ions** promote inflammation and metastasis [1] [2]

Aerobic glycolysis is not unique to tumour cells, as it’s a feature of rapidly dividing cells (immune cells and stem cells), that also use aerobic glycolysis to produce the intermediary metabolites of glycolysis as substrate for growth

The Warburg effect suggests a defect in oxidative phosphorylation, and the mitochondria in tumour cells are “structurally and functionally abnormal and incapable of generating normal levels of energy” [3].

* The story of oxidants and antioxidants in cancer is interesting.  ROS can be harmful for cancer: the immune system and the p53 genes use ROS to trigger apoptosis and tumour cells use antioxidants to protect themselves [4]; and Metformin protects against cancer and among other things, it selectively increases oxidative stress and apoptosis in tumour cells by promoting oxidative phosphorylation [5].  However, metastasis can be driven by ROS and mitochondrial catalase (an antioxidant enzyme) and other antioxidants reduce tumour progression and metastasis [6].

** Hydrogen ions are acidic and this is why proponents of dietary acid-base theories of cancer argue that an acidic environment promotes cancer growth.  However, our pH is tightly regulated and it's the elevated glycolysis in tumour cells that drives the local acidic environment rather than some dietary factor.

The Metabolic Theory of Cancer

The gene theory of cancer is the one most people are familiar with and it suggests that nuclear gene mutations initiates cancer, mitochondrial dysfunction, the Warburg Effect and other hallmarks of cancer; and that carcinogens primarily cause DNA damage that leads to the gene mutations.  An alternative theory, the ‘metabolic theory of cancer’, suggests that mitochondrial dysfunction is the primary cause of the gene mutations, Warburg effect and other hallmarks of cancer.  The evidence supporting mitochondrial dysfunction as a cause of cancer is described in detail in the paper Cancer as a Metabolic Disease, which I’ll summarise here:

  • Increased ROS production, as a result of mitochondrial dysfunction, can impair genome stability, tumor suppressor gene function, and control over cell proliferation
  • In humans, mitochondrial dysfunction precedes cancer an aerobic glycolysis
  • Mitochondrial dysfunction causes cancer cells to rely on aerobic glycolysis/substrate level phosphorylation, and a prolonged reliance on substrate level phosphorylation “produces genome instability, cellular disorder, and increased entropy i.e., characteristics of cancer”
  • The retrograde response is initiated in response to impaired mitochondrial functioning and “a prolonged RTG response, however, would leave the nuclear genome vulnerable to instability and mutability”
  • Mitochondrial dysfunction can increase HIF-1a (a signal of hypoxia), which increases angiogenesis and promotes inflammation, via impaired calcium homeostasis, ROS, inflammation (NFκB) and defects in oxidative phosphorylation increased
  • Some viruses can cause mitochondrial dysfunction and infected cells that survive a viral infection (don’t initiate apoptosis) upregulate substrate level phosphorylation
  • Transplanting healthy mitochondria into cybrid tumour cells suppresses tumour formation and growth, while transplanting nuclei from tumour cells into healthy cells has no effect
  • “Respiration is required for the emergence and maintenance of differentiation, while loss of respiration leads to glycolysis, dedifferentiation, and unbridled proliferation”.  (Remember that rapidly dividing cells use aerobic glycolysis for energy too.  Cells can be made stem-like by inhibiting oxidative phosphorylation)
  • Cells that can use substrate level phosphorylation for their energy needs can evade mitochondrial-induced apoptosis, but these may initiate apoptosis when their glucose supply is insufficient
  • Impaired calcium homeostasis, which can result from mitochondrial dysfunction, “could contribute to abnormalities in chromosomal segregation during mitosis”

The paper then discusses the ‘macrophage hypothesis of metastasis’: how metastatic tumour cells may be the result of a fusion between a tumour cell and a macrophage (tumour associated macrophages or TAMs), as metastatic tumour cells share many features with macrophages, in that they can infiltrate other tissues and promote inflammation.  The fusion with the macrophage also allows the metastatic tumour cell to evade the immune system

* In addition, it’s quite logical that mitochondrial dysfunction causes many of the hallmarks of cancer rather than the other way around seeing as mitochondria and mtDNA are more vulnerable to carcinogens, which also happen to damage/disrupt mitochondria

Other Mitochondrial Related Mechanisms

PTP1B

Mitochondrial dysfunction is strongly associated with and tends to cause ER stress (and vice versa) [7], which increases PTP1B [8].  PTP1B is a protein that is elevated in some cancers, seems to promote tumor growth and loss/inhibition of PTP1B is protective (but not completely) in animal models of cancer [9].

Insulin Resistance

Mitochondrial dysfunction can cause insulin resistance and insulin resistance increases both insulin and glucose levels in the blood.  Insulin resistance is associates with a poorer prognosis in breast cancer [10] and T2D, but not T1D, is associated with several cancers, likely due to hyperinsulinemia [11].  This might be because insulin resistance enhances sensitivity to the mitogenic (cell division promoting) effects of insulin [10].  High insulin and IGF-1 increase cell survival through the PI3K/Akt/mTOR pathway [12].  mTOR promotes cell proliferation and survival, is often elevated in cancer and correlates with cancer progression, adverse prognosis and resistance to chemotherapy [10]

* There are other causes of insulin resistance besides mitochondrial dysfunction (see here), but I included it here because it fits with the metabolic theme of the post

Further Reading:
(1) Cancer as a metabolic disease
(2) What Is The Origin of Cancer?
(3) Mitochondrial Dysfunction

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