Cancer is a disease of abnormal cellular metabolism, Part 3

September 18, 2010, Featured in Cancer and Natural Medicines, 0 Comments

Cancer cells need a lot of nutrients to multiply and survive. While much is understood about how cancer cells use blood sugar to make energy, not much is known about how they get other nutrients. Two related pathways are involved in cancer growth:

  1. The insulin/insulin-like growth factor-1 (IGF1) signaling pathway, which is activated when nutrients are available,
  2. The adenosine mono-phosphate-activated protein kinase (AMPK) pathway, activated when cells are starved for carbohydrates.

Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids. It is one of the two main mechanisms humans and many other animals use to keep blood glucose levels from dropping too low (hypoglycemia). The other means of maintaining blood glucose levels is through the degradation of glycogen (glycogenolysis).

Gluconeogenesis is a ubiquitous process, present in plants, animals, fungi, bacteria and other microorganisms. In animals, gluconeogenesis takes place mainly in the liver and, to a lesser extent, in the cortex of kidneys. This process occurs during periods of fasting, starvation, low-carbohydrate diets, or intense exercise and is highly endergonic. Gluconeogenesis is often associated with ketosis. Gluconeogenesis is also a target of therapy for type II diabetes, such as Metformin, which inhibits glucose formation and stimulates glucose uptake by cells.

Metformin exerts cardioprotective functions through AMPK activation and induction of catabolism [e.g. inhibitory phosphorylation of Acetyl-CoA Carboxylase (ACACA), a key protein involved in endogenous fatty acid synthesis] and/or inhibition of the anabolic promoter AKT. Concurrent blockade of oncogenic receptors such as HER2 with activation of AMPK-related catabolic pathways would represent highly efficacious tumor therapy capable of preventing, delaying and/or overcoming acquired resistance to HER2 inhibitor while decreasing risk of cardiomyopathy.

AMPK: a key regulator of energy balance in the single cell and the whole organism.

Metformin in cancer therapy: a new perspective for an old antidiabetic drug?

Metformin: a therapeutic opportunity in breast cancer.

Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells.

The antidiabetic drug metformin: a pharmaceutical AMPK activator to overcome breast cancer resistance to HER2 inhibitors while decreasing risk of cardiomyopathy.

The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level.

Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth.

Oncoproteins Akt and c-Myc regulate cell metabolism. Activation of either Akt or c-Myc leads to the Warburg effect as indicated by increased cellular glucose uptake, glycolysis, and lactate generation. When cells are treated with glycolysis inhibitors, Akt sensitizes cells to apoptosis, whereas c-Myc does not. In contrast, c-Myc but not Akt sensitizes cells to the inhibition of mitochondrial function. This is correlated with enhanced mitochondrial activities in c-Myc cells. Hence, although both Akt and c-Myc promote aerobic glycolysis, they differentially affect mitochondrial functions and render cells susceptible to the perturbation of cellular metabolic programs.

Akt and c-Myc differentially activate cellular metabolic programs and prime cells to bioenergetic inhibition.

Mammalian cells fuel their growth and proliferation through the catabolism of two main substrates: glucose and glutamine. Notwithstanding the renewed interest in the Warburg effect, cancer cells also depend on continued mitochondrial function for metabolism, specifically glutaminolysis that catabolizes glutamine to generate ATP and lactate.

Tumour cells need a constant supply of both energy and nitrogen substrates. Glutamine, the most abundant amino acid in the plasma, is the main physiological nitrogen vehicle between different mammalian tissues. Glutamine, which is highly transported into proliferating cells, is a major source for energy and nitrogen for biosynthesis, and a carbon substrate for anabolic processes in cancer cells. Cancer cells transport glutamine at a faster rate than normal cells across their plasmatic membranes by means of Na+-dependent A and ASC amino acid-transport systems, and across the inner mitochondrial membrane by a carrier-mediated system.

Glutamine is not only an important energy source in mitochondria, but is also a precursor of the brain neurotransmitter glutamate, which is likewise used for biosynthesis of the cellular antioxidant glutathione. Reactive oxygen species, such as superoxide anions and hydrogen peroxide, function as intracellular second messengers activating, among others, apoptosis, whereas glutamine is an apoptosis suppressor. In fact, it could contribute to block apoptosis induced by exogenous agents or by intracellular stimuli.

Glutamine at appropriate concentrations enhances a great number of cell functions via the activation of various transcription factors. The glutamine-responsive genes and the transcription factors involved correspond tightly to the specific effects of the amino acid in the inflammatory response, cell proliferation, differentiation and survival, and metabolic functions.The signalling pathways leading to the activation of transcription factors suggest that several kinases are involved, particularly mitogen-activated protein kinases.

Myc encodes a transcription factor c-Myc, which links altered cellular metabolism to tumorigenesis. c-Myc regulates genes involved in the biogenesis of ribosomes and mitochondria, and regulation of glucose and glutamine metabolism. Myc directly influences the expression of thousands of genes, of which, subsets are coordinately regulated with other transcription factors under specified conditions. Myc regulates entry into S phase by stimulating glucose and glutamine metabolism and mitochondrial biogenesis that are coupled to the regulation of E2F1 expression.

Myc is known to regulate miRNAs and stimulate cell proliferation, transcriptionally represses miR-23a and miR-23b, resulting in greater expression of their target protein, mitochondrial glutaminase (GLS). This leads to up-regulation of glutamine catabolism. GLS converts glutamine to glutamate that is further catabolized through the TCA cycle for the production of ATP or serves as substrate for glutathione synthesis. Myc might directly turn on the GLS gene. Myc is a master regulator of cell metabolism and proliferation. Inhibition of oncogene c-Myc by natural compounds effectively suppresses oncogenic transformation.

Glutamine addiction: a new therapeutic target in cancer.

MYC-induced cancer cell energy metabolism and therapeutic opportunities.

MYC, microRNAs and glutamine addiction in cancers.

c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism.

Finding an “Achilles’ heel” of cancer: the role of glucose and glutamine metabolism in the survival of transformed cells.

Glutamine in neoplastic cells: focus on the expression and roles of glutaminases.

Cancer metabolism: is glutamine sweeter than glucose?

Control of mammalian gene expression by amino acids, especially glutamine.

Glutamine and its relationship with intracellular redox status, oxidative stress and cell proliferation/death.

Contribution by different fuels and metabolic pathways to the total ATP turnover of proliferating MCF-7 breast cancer cells.

PI3K (phosphoinositol 3-kinase) and its downstream effector AKT play a direct role in stimulating glucose uptake and metabolism, rendering the transformed cell addicted to glucose for the maintenance of survival. In contrast, less is known about the regulation of glutamine uptake and metabolism.

Myc coordinates the expression of genes necessary for cells to engage in glutamine catabolism that exceeds the cellular requirement for protein and nucleotide biosynthesis. A consequence of this Myc-dependent glutaminolysis is the reprogramming of mitochondrial metabolism to depend on glutamine catabolism to sustain cellular viability and TCA cycle anapleurosis. The ability of Myc-expressing cells to engage in glutaminolysis does not depend on concomitant activation of PI3K or AKT. The stimulation of mitochondrial glutamine metabolism resulted in reduced glucose carbon entering the TCA cycle and a decreased contribution of glucose to the mitochondrial-dependent synthesis of phospholipids. Myc induces a transcriptional program that promotes glutaminolysis and triggers cellular addiction to glutamine as a bioenergetic substrate.

The metabolic enzyme glutaminase (GLS) catalyzes the hydrolysis of glutamine to glutamate. Transformed fibroblasts and cancer cells exhibit elevated glutaminase (GLS) activity that is dependent on Rho GTPases and NF-κB activity. Inhibition of glutaminase (GLS) expression decreases growth and tumourigenicity of tumour cells.

The idea that conversion of glucose to ATP is an attractive target for cancer therapy has been supported in part by the observation that glucose deprivation induces apoptosis in rodent cells transduced with the proto-oncogene Myc, but not in the parental line. Recent study shows depletion of glucose killed normal human cells irrespective of induced Myc activity and by a mechanism different from apoptosis. However, depletion of glutamine, another major nutrient consumed by cancer cells, induced apoptosis depending on Myc activity. This apoptosis was preceded by depletion of the Krebs cycle intermediates, was prevented by two Krebs cycle substrates, but was unrelated to ATP synthesis or several other reported consequences of glutamine starvation. These results suggest that the fate of normal human cells should be considered in evaluating nutrient deprivation as a strategy for cancer therapy, and that understanding how glutamine metabolism is linked to cell viability might provide new approaches for treatment of cancer.

Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction.

Targeting mitochondrial glutaminase activity inhibits oncogenic transformation.

Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells.

The c-Myc gene is amplified in 85-95% all cancers, including lung cancer, breast cancer, and rare cases of colon cancer. In addition, elevated expression of the c-Myc gene is found in almost one-third of breast and colon cancers. The frequency of genetic alterations of c-Myc in human cancers has allowed estimation that approximately 70,000 U.S. cancer deaths per year are associated with changes in the c-Myc gene or its expression. c-Myc may contribute to one-seventh of U.S. cancer deaths.

Thus, it is now known that that c-Myc is an important regulator of glucose and glutamine metabolism, cell cycle, growth, apoptosis, and its dysregulated expression is associated with many cancers. Myc is instrumental in directly or indirectly regulating the progression through the G1 phase and G1/S transition, and transformation by Myc results in perturbed cell cycle.

Butein is a flavonoid isolated from the bark of Rhus verniciflua Stokes and the flowers of Butea monosperma, and is known to be a potential therapeutic drug for treating inflammation and cancer. Butein suppresses expression of c-Myc at the transcriptional level and down-regulates DNA-binding activity. Butein also suppress the activation of Akt and NF-kB. Remember, NF-kB stimulates c-Myc expression in cancers. Curcumin and Genistein also suppress expression of c-Myc.

Butein suppresses c-Myc-dependent transcription and Akt-dependent phosphorylation of hTERT in human leukemia cells.

Butein downregulates chemokine receptor CXCR4 expression and function through suppression of NF-kappaB activation in breast and pancreatic tumor cells.

Butein, a tetrahydroxychalcone, inhibits nuclear factor (NF)-kappaB and NF-kappaB-regulated gene expression through direct inhibition of IkappaBalpha kinase beta on cysteine 179 residue.

Butein sensitizes human hepatoma cells to TRAIL-induced apoptosis via extracellular signal-regulated kinase/Sp1-dependent DR5 upregulation and NF-kappaB inactivation.

Butein induces G(2)/M phase arrest and apoptosis in human hepatoma cancer cells through ROS generation.

Butein suppresses constitutive and inducible signal transducer and activator of transcription (STAT) 3 activation and STAT3-regulated gene products through the induction of a protein tyrosine phosphatase SHP-1.

A novel anticancer effect of butein: inhibition of invasion through the ERK1/2 and NF-kappa B signaling pathways in bladder cancer cells.

Regulation of c-myc gene by nitric oxide via inactivating NF-kappa B complex in P19 mouse embryonal carcinoma cells.

Curcumin inhibits the Sonic Hedgehog signaling pathway and triggers apoptosis in medulloblastoma cells.

Genistein represses telomerase activity via both transcriptional and posttranslational mechanisms in human prostate cancer cells.

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