Cancer cells want high fat and an attack on the Pancreas

High Fat is what cancer cell wants

One feature that distinguishes tumor cells from normal cells is their dysregulated metabolism. For example, tumor cells undergo glycolytic rather than oxidative metabolism, a change known as the Warburg effect, and they synthesize greater amounts of proteins and fatty acids than do normal cells (see the commentary by Yecies and Manning).

Connie’s notes: Cancer cells use MAGL and LIPE and Insulin inhibits LIPE.

Sci. Signal.  12 Jan 2010:
Vol. 3, Issue 104, pp. ec8
DOI: 10.1126/scisignal.3104ec8

  • The authors found that monoacylgycerol lipase (MAGL), a serine hydrolase that degrades the endogenous cannabinoid 2-arachidonylglycerol and other MAGs, was enriched in the aggressive cell lines. MAGL was also more abundant in high-grade, human ovarian tumors than in benign tumors. Knockdown of MAGL in aggressive cancer cell lines by short hairpin RNA (shRNA) resulted in decreased amounts of free fatty acids (FFAs) and inhibited the migration, survival, and invasiveness of the cells, as assessed in vitro; conversely, lentiviral-mediated overexpression of MAGL in nonaggressive cancer cell lines had opposing effects. Transfer of an aggressive melanoma cell line containing MAGL-specific shRNA into immune-deficient mice resulted in smaller tumors than occurred when control shRNA-treated cells were used; however, the effect of knockdown of MAGL on tumor growth was reversed when the mice were fed a high-fat diet. Lipidomic analysis revealed the increased abundance of protumorigenic lipids, such as lysophosphatidic acid and prostaglandin E2, in aggressive cell lines, and blockade of the receptors for these lipids decreased the migration of these cell lines in vitro. Together, these data suggest that tumor cells use MAGL to generate a range of protumorigenic lipid signals that increase malignancy.

http://stke.sciencemag.org/content/3/104/ec8

Monoacylglycerol lipase functions together with hormone-sensitive lipase (LIPE)

  • Monoacylglycerol lipase functions together with hormone-sensitive lipase (LIPE) to hydrolyze intracellular triglyceride stores in adipocytes and other cells to fatty acids and glycerol. MGLL may also complement lipoprotein lipase (LPL) in completing hydrolysis of monoglycerides resulting from degradation of lipoprotein triglycerides.[5]
  • Monoacylglycerol lipase is a key enzyme in the hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG).[6][7] It converts monoacylglycerols to the free fatty acid and glycerol. The contribution of MAGL to total brain 2-AG hydrolysis activity has been estimated to be ~85% (ABHD6 and ABHD12 are responsible for ~4% and ~9%, respectively, of the remainder),[8][9] and this in vitro estimate has been confirmed in vivo by the selective MAGL inhibitor JZL184.[10] Chronic inactivation of MAGL results in massive (>10-fold) elevations of brain 2-AG in mice, along with marked compensatory downregulation of CB1 receptors in selective brain areas.[

Hormone-sensitive lipase mobilizes stored fats

  • The main function of hormone-sensitive lipase is to mobilize the stored fats. Mobilization and Cellular Uptake of Stored Fats (with Animation) HSL functions to hydrolyze the first fatty acid from a triacylglycerol molecule, freeing a fatty acid and diglyceride. It is also known as triglyceride lipase, while the enzyme that cleaves the second fatty acid in the triglyceride is known as diglyceride lipase, and the third enzyme that cleaves the final fatty acid is called monoglyceride lipase. Only the initial enzyme is affected by hormones, hence its hormone-sensitive lipase name. The diglyceride and monoglyceride enzymes are tens to hundreds of times faster, hence HSL is the rate-limiting step in cleaving fatty acids from the triglyceride molecule.[8][9]
  • HSL is activated when the body needs to mobilize energy stores, and so responds positively to catecholamines, ACTH. It is inhibited by insulin. Previously, glucagon was thought to activate HSL, however the removal of insulin’s inhibitory effects (“cutting the brakes”) is the source of activation. The lipolytic effect of glucagon in adipose tissue is minimal in humans.[citation needed]
  • Another important role is the release of cholesterol from cholesterol esters for use in the production of steroids.[10

HCL is inhibited by insulin

  • Insulin (from the Latin, insula meaning island) is a peptide hormone produced by beta cells of the pancreatic islets, and by the Brockmann body in some teleost fish.[3] It has important effects on the metabolism of carbohydrates, fats and protein by promoting the absorption of, especially, glucose from the blood into fat, liver and skeletal muscle[4] In these tissues the absorbed glucose is converted into either glycogen or fats (triglycerides), or, in the case of the liver, into both.[4] Glucose production (and excretion into the blood) by the liver is strongly inhibited by high concentrations of insulin in the blood.[5] Circulating insulin also affects the synthesis of proteins in a wide variety of tissues. In high concentrations in the blood it is therefore an anabolic hormone, promoting the conversion of small molecules in the blood into large molecules inside the cells. Low insulin levels in the blood have the opposite effect by promoting widespread catabolism.
  • The pancreatic beta cells (β cells) are known to be sensitive to the glucose concentration in the blood. When the blood glucose levels are high they secrete insulin into the blood; when the levels are low they cease their secretion of this hormone into the general circulation.[6] Their neighboring alpha cells, probably by taking their cues from the beta cells,[6] secrete glucagon into the blood in the opposite manner: high secretion rates when the blood glucose concentrations are low, and low secretion rates when the glucose levels are high.[4][6] High glucagon concentrations in the blood plasma powerfully stimulate the liver to release glucose into the blood by glycogenolysis and gluconeogenesis, thus having the opposite effect on the blood glucose level to that produced by high insulin concentrations.[4][6] The secretion of insulin and glucagon into the blood in response to the blood glucose concentration is the primary mechanism responsible for keeping the glucose levels in the extracellular fluids within very narrow limits at rest, after meals, and during exercise and starvation.[6]
  • When the pancreatic beta cells are destroyed by an autoimmune process, insulin can no longer be synthesized or be secreted into the blood. This results in type 1 diabetes mellitus, which is characterized by very high blood sugar levels, and generalized body wasting, which is fatal if not treated. This can only be corrected by injecting the hormone, either directly into the blood if the patient is very ill and confused or comatosed, or subcutaneously for routine maintenance therapy, which must be continued for the rest of the person’s life.[7] The exact details of how much insulin needs to be injected, and when during the day, has to be adjusted according to the patient’s daily routine of meals and exercise, in order to mimic the physiological secretion of insulin as closely as is practically possible.

 

Summary of Cancer Metabolism

  • Reprogrammed metabolic pathways are essential for cancer cell survival and growth.
  • Frequently reprogrammed activities include those that allow tumor cells to take up abundant nutrients and use them to produce ATP, generate biosynthetic precursors and macromolecules, and tolerate stresses associated with malignancy (for example, redox stress and hypoxia).
  • An emerging class of reprogrammed pathways includes those allowing cancer cells to tolerate nutrient depletion by catabolizing macromolecules from inside or outside the cell (for example, autophagy, macropinocytosis, and lipid scavenging).
  • Reprogramming may be regulated intrinsically by tumorigenic mutations in cancer cells or extrinsically by influences of the microenvironment.
  • Oncometabolites (for example, 2HG) accumulate as a consequence of genetic changes within a tumor and contribute to the molecular process of malignant transformation.
  • Many metabolites exert their biological effects outside of the classical metabolic network, affecting signal transduction, epigenetics, and other functions.
  • New approaches to assess metabolism in living tumors in humans and mice may improve our ability to understand how metabolic reprogramming is regulated and which altered pathways hold opportunities to improve care of cancer patients.

 

  1. First, metabolic reprogramming is essential for the biology of malignant cells, particularly their ability to survive and grow by using conventional metabolic pathways to produce energy, synthesize biosynthetic precursors, and maintain redox balance.
  2. Second, metabolic reprogramming is the result of mutations in oncogenes and tumor suppressors, leading to activation of PI3K and mTORC1 signaling pathways and transcriptional networks involving HIFs, MYC, and SREBP-1.
  3. Third, alterations in metabolite levels can affect cellular signaling, epigenetics, and gene expression through posttranslational modifications such as acetylation, methylation, and thiol oxidation.
  4. Fourth, taken together, studies on cultured cells have demonstrated a remarkable diversity of anabolic and catabolic pathways in cancer, with induction of autophagy and utilization of extracellular lipids and proteins complementing the classical pathways like glycolysis and glutaminolysis.

Tumor-suppressive functions of p53

Another commonly deregulated pathway in cancer is gain of function of MYC by chromosomal translocations, gene amplification, and single-nucleotide polymorphisms. MYC increases the expression of many genes that support anabolic growth, including transporters and enzymes involved in glycolysis, fatty acid synthesis, glutaminolysis, serine metabolism, and mitochondrial metabolism (18). Oncogenes like Kras, which is frequently mutated in lung, colon, and pancreatic cancers, co-opt the physiological functions of PI3K and MYC pathways to promote tumorigenicity. Aside from oncogenes, tumor suppressors such as the p53 transcription factor can also regulate metabolism (19). The p53 protein–encoding gene TP53 (tumor protein p53) is mutated or deleted in 50% of all human cancers. The tumor-suppressive functions of p53 have been ascribed to execution of DNA repair, cell cycle arrest, senescence, and apoptosis. However, recent studies indicate that p53 tumor-suppressive actions might be independent of these canonical p53 activities but rather dependent on the regulation of metabolism and oxidative stress (20, 21). Loss of p53 increases glycolytic flux to promote anabolism and redox balance, two key processes that promote tumorigenesis.

Mitochondrial metabolism

Mitochondrial metabolism has also emerged as a key target for cancer therapy, in part, due to the revelation that the antidiabetic drug metformin is an anticancer agent (153). Numerous epidemiological studies first suggested that diabetic patients taking metformin, to control their blood glucose levels, were less likely to develop cancer and had an improved survival rate if cancer was already present (154). Laboratory-based studies have also provided evidence that metformin may serve as an anticancer agent (155–157). Biochemists recognized that metformin reversibly inhibits mitochondrial complex I (158–160). Recent studies indicate that metformin acts as an anticancer agent by inhibiting mitochondrial ETC complex I (161). Specifically, metformin inhibits mitochondrial ATP production, inducing cancer cell death when glycolytic ATP levels diminish as a result of limited glucose availability.

Metformin

Metformin also inhibits the biosynthetic capacity of the mitochondria to generate macromolecules (lipids, amino acids, and nucleotides) within cancer cells (162). The remarkable safety profile of metformin is due to its uptake by organic cation transporters (OCTs), which are only present in a few tissues, such as the liver and kidney (163). Certain tumor cells also express OCTs to allow the uptake of metformin (164). However, in the absence of OCTs, tumors would not accumulate metformin to inhibit mitochondrial complex I. Ongoing clinical trials using metformin as an anticancer agent should assess the expression levels of OCTs to identify the tumors with highest expression, which are likely to be susceptible to metformin.

Vitamin C

An interesting approach to depleting NADPH levels and increasing ROS is to administer high doses of vitamin C (ascorbate). Vitamin C is imported into cells through sodium-dependent vitamin C transporters, whereas the oxidized form of vitamin C, dehydroascorbate (DHA), is imported into cells through glucose transporters such as GLUT1 (179). When the cell takes up DHA, it is reduced back to vitamin C by glutathione (GSH), which consequently becomes GSSG. Subsequently, GSSG is converted back to GSH by NADPH-dependent GR. Because the blood is an oxidizing environment, vitamin C becomes oxidized to DHA before being taken up by the cell. Thus, high doses of vitamin C diminish the tumorigenesis of colorectal tumors that harbor oncogenic KRAS mutations and express high levels of GLUT1 by depleting the NADPH and GSH pools and consequently increasing ROS levels to induce cancer cell death (179, 180). Vitamin C administered at high doses intravenously is safe in humans and, in conjunction with conventional paclitaxel-carboplatin therapy, demonstrated a benefit in a small number of patients (181). Additional strategies to diminish GSH include the administration of buthionine sulfoximine, an irreversible inhibitor of γ-glutamylcysteine synthetase, which can be safely administered to humans and is efficacious in preclinical tumor models (182). Moreover, glutathione is a tripeptide consisting of cysteine, glutamate, and glycine. Thus, decreasing glutamate levels using glutaminase inhibitors or diminishing cysteine levels by preventing extracellular cysteine (two linked cysteine molecules) uptake can also raise ROS levels in cancer cells to induce cell death.

 

Scientists are finding way to target cancer cells using their metabolic pathways

Another potential therapeutic strategy to inhibit mitochondrial metabolism in certain tumors would be to use autophagy or glutaminase inhibitors. Autophagy provides amino acids, such as glutamine, that fuel the TCA cycle in NSCLC and pancreatic cancers, and short-term autophagy inhibition has been shown to decrease tumor progression without incurring systemic toxicity in mouse models of NSCLC (168169). Some tumors are addicted to using glutamine to support TCA cycle metabolism even in the absence of autophagy; thus, glutaminase inhibitors can reduce tumor burden in these models (475,170). An alternative approach is to target acetate metabolism. Although a major function of the mitochondria is to provide acetyl-CoA to the cell, cancer cells can also use acetate to support cell growth and survival during metabolic stress (hypoxia or nutrient deprivation) (96171). The cytosolic enzyme acetyl-CoA synthase 2 (ACCS2), which converts acetate to acetyl-CoA, is dispensable for normal development; thus, ACCS2 is a promising target of acetate metabolism. ACCS2 knockout mice do not display overt pathologies, but genetic loss of ACCS2 reduces tumor burden in models of hepatocellular carcinoma (171). Human glioblastomas can oxidize acetate and may be sensitive to inhibitors of this process (172). Thus, targeting metabolism with inhibitors of autophagy, acetate metabolism, and other pathways that supply key metabolic intermediates may be efficacious in some contexts.

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