Tumor suppressors and cell metabolism: a recipe for cancer growth

In the paper

“tumor cells, in order to meet the increased requirements of proliferation, often display fundamental changes in pathways of energy metabolism and nutrient uptake (Garber 2006).”

What the sources say

• Not checked yetcites Garber 2006

In the paper

“tumor cells preferentially use glycolysis over mitochondrial oxidative phosphorylation (OXPHOS) for glucose-dependent ATP production even in the presence of ample oxygen to fuel mitochondrial respiration, a phenomenon known as the ''Warburg effect'' (Warburg 1956).”

• Also stated in: § Glycolysis-metabolic reprogramming fuels cell growth and proliferation · plain

  “One of the primary metabolic changes associated with proliferating tumor cells is induction of aerobic glycolysis (Fig. 1).”

What the sources say

• Not checked yetcites Warburg 1956

In the paper

“supporting the theory that alterations in cellular metabolism may contribute to the malignant phenotype.”

In the paper

“AMPK appears to function across evolution as a low energy checkpoint, triggering multiple biological adaptations designed to preserve energy and adapt to metabolic stress before the cell reaches a state of bioenergetic catastrophe that triggers cell death.”

In the paper

“Despite the low overall percentage of pyruvate available for mitochondrial synthesis, the high rate of glycolytic flux provides sufficient amounts for biosynthesis.”

In the paper

“To meet this challenge, metabolic activities are reorganized in proliferating cells resulting in an anabolic shift in cellular metabolism.”

In the paper

“leading to the theory that oncogene and tumor suppressor networks influence the metabolic shift in cancer.”

In the paper

“Without such a strategy, cells undergo apoptosis.”

In the paper

“In particular, the c-Myc proto-oncogene is a potent regulator of multiple metabolic pathways essential for cancer growth (Dang et al. 2008).”

What the sources say

• Not checked yetcites Dang et al. 2008

In the paper

“Metabolic flux analysis has revealed that glutamine is used by proliferating cells to generate a pool of a-ketoglutarate, which can be metabolized through the TCA cycle to regenerate the OAA consumed by biosynthesis (DeBerardinis et al. 2007).”

What the sources say

• Not checked yetcites DeBerardinis et al. 2007

In the paper

“Thus, in addition to its role as cellular energy center, the mitochondrion takes up a new role as a biosynthetic hub to meet the increased biosynthetic demand during proliferation, converting metabolites such as pyruvate and glutamine into intermediates utilized by other biosynthetic pathways (Fig. 1).”

In the paper

“Recent data suggest that pyruvate kinase-M2 (PK-M2), an isoform of the rate-limiting enzyme for pyruvate generation that is preferentially expressed in tumor cells, regulates the flux of carbon into Rib-5-P and nucleotide synthesis (Christofk et al. 2008a).”

What the sources say

• Not checked yetcites Christofk et al. 2008a

In the paper

“LKB1 is required for AMPK activation under conditions of bioenergetic stress including glucose withdrawal (Hawley et al. 2003;Woods et al. 2003;Shaw et al. 2004b).”

What the sources say

• Not checked yetcites Hawley et al. 2003
• Not checked yetcites Woods et al. 2003
• Not checked yetcites Shaw et al. 2004b

In the paper

“The AMP-activated protein kinase (AMPK) is a highly conserved heterotrimeric protein kinase complex that plays a central role in the regulation of cellular energy homeostasis, tethering the bioenergetic state of a cell to a number of critical biological functions aimed at preserving cellular energy and viability (Hardie 2007).”

What the sources say

• Not checked yetcites Hardie 2007

In the paper

“In contrast, the bioenergetic sensor AMP-activated protein kinase (AMPK) phosphorylates the TSC1-TSC2 complex in an LKB-dependent fashion to promote mTOR inhibition (Inoki et al. 2003).”

What the sources say

• Not checked yetcites Inoki et al. 2003

In the paper

“In addition to energy, glycolysis generates metabolic intermediates important for cell growth.”

In the paper

“This may explain why glutamine is an essential metabolite for proliferation (Griffiths and Keast 1990).”

What the sources say

• Not checked yetcites Griffiths and Keast 1990

In the paper

“Thus, maintaining high rates of glycolysis allows cells to meet the energetic and biosynthetic demands of anabolic growth.”

In the paper

“several of the mutations that lead to cancer also drive the altered metabolism of tumor cells (Vogelstein and Kinzler 2004).”

What the sources say

• Not checked yetcites Vogelstein and Kinzler 2004

In the paper

“However, cell proliferation requires that bioenergetic resources and biosynthetic activity be redirected toward the duplication of all macromolecular components (DNA, membranes, and proteins) to ensure successful passage through the cell cycle.”

In the paper

“By converting pyruvate to lactate, LDH-A recovers the NAD + needed to maintain glycolysis.”

In the paper

“Many prominent oncogenes including c-Myc, H-ras, src, and Akt stimulate anabolic metabolism in transformed cells (Dang and Semenza 1999;Elstrom et al. 2004).”

What the sources say

• Not checked yetcites Dang and Semenza 1999
• Not checked yetcites Elstrom et al. 2004

In the paper

“The majority of macromolecules required for proliferation (i.e., lipids, proteins, and nucleic acids) are generated de novo from glucose (Bauer et al. 2005).”

What the sources say

• Not checked yetcites Bauer et al. 2005

In the paper

“Although the energetic yield per molecule of glucose is much lower for aerobic glycolysis compared with OXPHOS, when glucose is in excess and flux through the pathway high, glycolysis has the potential to produce ATP in greater quantities and at a faster rate (Guppy et al. 1993).”

What the sources say

• Not checked yetcites Guppy et al. 1993

In the paper

“Many of the predominant mutations observed in cancer also control tumor cell metabolism (Vogelstein and Kinzler 2004)”

What the sources say

• Not checked yetcites Vogelstein and Kinzler 2004

In the paper

“As a growing tumor with increased metabolic demands outstrips nutrient supply, it must enact a strategy to maintain cellular bioenergetics lest cell growth, proliferation, or viability be affected.”

In the paper

“The decision to proliferate presents a significant bioenergetic challenge for a cell.”

In the paper

“However, increased metabolic potential, while beneficial for unchecked growth, poses an inherent challenge for malignant cells.”

In the paper

“By regulating the amount of pyruvate generated by glycolysis, PK-M2 functions to direct the flow of carbon into pathways of nucleotide and fatty acid biosynthesis that support the proliferation of tumor cells.”

In the paper

“inhibition of mTOR-dependent protein translation through the regulation of the TSC1-TSC2 complex or the mTORbinding protein Raptor (Inoki et al. 2003;Corradetti et al. 2004;Shaw et al. 2004a;Gwinn et al. 2008)”

What the sources say

• Not checked yetcites Inoki et al. 2003
• Not checked yetcites Corradetti et al. 2004
• Not checked yetcites Shaw et al. 2004a

In the paper

“This step is critical for the maintenance of tumor proliferation in vivo (Fantin et al. 2006).”

What the sources say

• Not checked yetcites Fantin et al. 2006

In the paper

“Interestingly, the enzymatic activity of PK-M2 is negatively regulated by phosphotyrosine signaling downstream from growth receptors (Christofk et al. 2008b).”

What the sources say

• Not checked yetcites Christofk et al. 2008b

In the paper

“These include inhibition of lipid synthesis by Acetyl-CoA carboxylase-1 (ACC1) phosphorylation (Davies et al. 1990)”

What the sources say

• Not checked yetcites Davies et al. 1990 source

In the paper

“Together, mutations in PI3K signaling constitute one of the most common sets of mutations in human tumors (Shaw and Cantley 2006).”

What the sources say

• Not checked yetcites Shaw and Cantley 2006

In the paper

“Akt regulates mTOR function by phosphorylating and inhibiting TSC2, which in turn disrupts the function of the TSC1-TSC2 complex, promoting mTOR activation (Inoki et al. 2002).”

What the sources say

• Not checked yetcites Inoki et al. 2002

In the paper

“Glucose is a critical nutrient for proliferating cells (Holley and Kiernan 1974;Pardee 1974).”

What the sources say

• Not checked yetcites Holley and Kiernan 1974
• Not checked yetcites Pardee 1974

In the paper

“The emergence of metabolic enzymes (i.e., PK-M2, LDHA, SDH, FH, PDK1, and IDH1) as important regulators of cancer cell growth suggests that metabolic control is a key element of tumor progression.”

In the paper

“When combined with the loss of tumor suppressors that promote metabolic adaptation, cancer cells risk developing greater sensitivity to bio-energetic stress.”

In the paper

“Oncogenic pathways that promote proliferation and survival in normal cells confer ''metabolic permission'' in transformed cells by stimulating bioenergetic pathways and anabolic growth.”

In the paper

“The importance of autophagy in tumor suppression may actually stem from its role in the degradation of long-lived proteins and organelles, rather than its role in stress responses.”

In the paper

“while cytoplasmic p53 appears to function as a negative regulator of autophagy (Tasdemir et al. 2008a,b).”

What the sources say

• Not checked yetcites Tasdemir et al. 2008a,b

In the paper

“From this logic, oncogenedriven signal transduction may promote greater dependence on specific metabolic pathways such as glycolysis to maintain tumor growth.”

In the paper

“AMPK-dependent p53 activation negatively regulates cell cycle progression via the cyclin-dependent kinase (cdk) inhibitor p21.”

In the paper

“Intracellular sensors of energy, nutrients, and oxygen promote metabolic adaptation to stress during tumorigenesis.”

In the paper

“or through the regulation of macroautophagy (Buzzai et al. 2007; J. Liang et al. 2007;Lippai et al. 2008).”

What the sources say

• Not checked yetcites Buzzai et al. 2007
• Not checked yetcites J. Liang et al. 2007 source
• Not checked yetcites Lippai et al. 2008 source

In the paper

“Reprogramming of core metabolism in tumors confers a selective growth advantage (i.e., enhanced proliferation, resistance to apoptosis) that promotes tumor progression.”

In the paper

“Beclin-1 haploinsufficiency promotes tumorigenesis in mouse models and is associated with breast and ovarian cancers in humans (Aita et al. 1999;Liang et al. 1999;Qu et al. 2003).”

What the sources say

• Not checked yetcites Aita et al. 1999
• Not checked yetcites Liang et al. 1999
• Not checked yetcites Qu et al. 2003

In the paper

“However, the fact that metabolic enzymes such as SDH and FH function as tumor suppressors in humans suggests that metabolic deregulation can be an initiating event in cancer.”

In the paper

“The interaction of AMPK with several transcription factors indicates that transcriptional regulation may be central to AMPK-dependent stress responses.”

In the paper

“Oncogene pathways including Akt, mTOR, and Bcl2 appear to function as inhibitors of autophagy, while tumor suppressors including PTEN, TSC2, LKB1, and HIF1a promote autophagy (Maiuri et al. 2009).”

What the sources say

• Not checked yetcites Maiuri et al. 2009

In the paper

“which may explain why metformin, an antidiabetic therapy, can be anti-tumorigenic (Evans et al. 2005;Huang et al. 2008).”

What the sources say

• Not checked yetcites Evans et al. 2005
• Not checked yetcites Huang et al. 2008

In the paper

“Studies involving Beclin-1, which is required for autophagy induction in mammalian cells, suggest that autophagy functions as an important tumor suppressor mechanism.”

In the paper

“As a consequence, tumor cells must undergo a period of metabolic adaptation to survive this metabolic stress or undergo apoptosis.”

In the paper

“Low O 2 , ROS, or accumulation of the TCA substrates succinate or fumarate promotes HIF1a protein stabilization and transcriptional activity.”

In the paper

“This metabolic stress response is reinforced by the p53 target genes sestrin1 and sestrin2, which activate AMPK as part of a feedback loop (Budanov and Karin 2008).”

What the sources say

• Not checked yetcites Budanov and Karin 2008

In the paper

“Oncogene pathways including Akt, mTOR, and Bcl2 appear to function as inhibitors of autophagy, while tumor suppressors including PTEN, TSC2, LKB1, and HIF1a promote autophagy (Maiuri et al. 2009).”

What the sources say

• Not checked yetcites Maiuri et al. 2009

In the paper

“p53 activation has been shown to promote autophagy in response to stress through transcriptional control of autophagy regulators such as DRAM (Crighton et al. 2006)”

What the sources say

• Not checked yetcites Crighton et al. 2006

In the paper

“The emergence of metabolic enzymes (i.e., PK-M2, LDHA, SDH, FH, PDK1, and IDH1) as important regulators of cancer cell growth suggests that metabolic control is a key element of tumor progression.”

In the paper

“The metabolic response of an individual tumor cell is dependent on both the combination of oncogenic and/or tumor suppressor mutations and the environmental conditions (nutrient depletion, hypoxia) encountered within the tumor microenvironment.”

In the paper

“While much attention has been paid to the prevalence of aerobic glycolytic ''Warburg'' metabolism in cancer, the metabolic pathways that support cell growth during tumorigenesis are likely far more complex.”

In the paper

“Oncogenic transformation or loss of tumor suppressor function drives unchecked growth and proliferation in cancer cells, which often coincide with both an increase in bioenergetic potential and the ability to take up nutrients in a cell-autonomous fashion.”

In the paper

“Beclin-1 haploinsufficiency promotes tumorigenesis in mouse models and is associated with breast and ovarian cancers in humans (Aita et al. 1999;Liang et al. 1999;Qu et al. 2003).”

What the sources say

• Not checked yetcites Aita et al. 1999
• Not checked yetcites Liang et al. 1999
• Not checked yetcites Qu et al. 2003

In the paper

“Thus, the role of p53 in autophagy induction may depend on its cellular localization, transcriptional activity, and mechanism of activation.”

In the paper

“Tumor suppressors such as p53, LKB1, and TSC2 function as a brake on cell growth by antagonizing many of the same biosynthetic pathways stimulated by oncogenes under conditions of limiting intracellular glucose or amino acid supplies.”

In the paper

“while antiapoptotic Bcl-2 inhibits Beclin-1 function (Pattingre et al. 2005).”

What the sources say

• Not checked yetcites Pattingre et al. 2005

In the paper

“Activation of the tumor suppressor p53 by AMPK promotes physiological adaptation to metabolic stress by multiple mechanisms.”

In the paper

“Angiogenesis and neovascularization of the tumor is one strategy of metabolic adaptation used by tumors to relieve this stress.”

In the paper

“A solid tumor can outstrip its nutrient and oxygen supply as it grows, resulting in metabolic stress (tumors experiencing metabolic stress are depicted in gray).”

In the paper

“Oncogenic transformation or loss of tumor suppressor function drives unchecked growth and proliferation in cancer cells, which often coincide with both an increase in bioenergetic potential and the ability to take up nutrients in a cell-autonomous fashion.”

In the paper

“which may explain why metformin, an antidiabetic therapy, can be anti-tumorigenic (Evans et al. 2005;Huang et al. 2008).”

In the paper

“Moreover, the ability of tumor cells to survive metabolic stress in vivo requires AMPK-dependent activation of p53 (Buzzai et al. 2007)”

What the sources say

• Not checked yetcites Buzzai et al. 2007

In the paper

“As with metabolic transformation, oncogene and tumor suppressor pathways display opposing effects on autophagy.”

What the sources say

• Not checked yetcites Maiuri et al. 2009

In the paper

“Impairment of glycolytic flux by TIGAR, combined with increased activation of b-oxidation and electron transport through expression of carnitine palmitoyltransferase Ic (Cpt1c) and SCO2, respectively, results in a p53-dependent metabolic shift toward OXPHOS.”