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Lipid Droplets: A Key Cellular Organelle Associated with Cancer Cell Survival under Normoxia and Hypoxia

View Article: PubMed Central - PubMed

ABSTRACT

The Warburg effect describes the phenomenon by which cancer cells obtain energy from glycolysis even under normoxic (O2-sufficient) conditions. Tumor tissues are generally exposed to hypoxia owing to inefficient and aberrant vasculature. Cancer cells have multiple molecular mechanisms to adapt to such stress conditions by reprogramming the cellular metabolism. Hypoxia-inducible factors are major transcription factors induced in cancer cells in response to hypoxia that contribute to the metabolic changes. In addition, cancer cells within hypoxic tumor areas have reduced access to serum components such as nutrients and lipids. However, the effect of such serum factor deprivation on cancer cell biology in the context of tumor hypoxia is not fully understood. Cancer cells are lipid-rich under normoxia and hypoxia, leading to the increased generation of a cellular organelle, the lipid droplet (LD). In recent years, the LD-mediated stress response mechanisms of cancer cells have been revealed. This review focuses on the production and functions of LDs in various types of cancer cells in relation to the associated cellular environment factors including tissue oxygenation status and metabolic mechanisms. This information will contribute to the current understanding of how cancer cells adapt to diverse tumor environments to promote their survival.

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Schematic of the possible metabolic routes associated with lipid droplet (LD) synthesis in cancer cells exposed to normoxic conditions. Under normoxia, cancer cells are expected to have easy access to serum components. Such factors (O2, glucose, glutamine, and lipids) are designated by a larger font size compared with that of lactate. Major metabolic energy sources (glycolysis and β-oxidation) are depicted with star bursts. Metabolic routes (1–16) possibly associated with LD synthesis and β-oxidation are designated with red and blue arrows, respectively. Other routes are shown in black arrows. The abbreviations used are as follows: LDs = lipid droplets; ER = endoplasmic reticulum; HIFs = hypoxia inducible factors; ARNT = arylhydrocarbon receptor nuclear translocator; Ac-CoA = acetyl coenzyme A; LCFAs = long chain fatty acids; FABPs = fatty acid binding proteins; PPARs = peroxisome proliferator-activated receptors; LXRs = liver X receptors; SREBPs = sterol regulatory element binding proteins; RXR = retinoid X receptor; FASN = fatty acid synthase; SCD-1 = stearoyl CoA desaturase-1; LDL-R = low-density lipoprotein receptor; EVs = extracellular vesicles. The symbols used are as follows: : LCFAs, : cholesterol, : transporter, : receptor.
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ijms-17-01430-f001: Schematic of the possible metabolic routes associated with lipid droplet (LD) synthesis in cancer cells exposed to normoxic conditions. Under normoxia, cancer cells are expected to have easy access to serum components. Such factors (O2, glucose, glutamine, and lipids) are designated by a larger font size compared with that of lactate. Major metabolic energy sources (glycolysis and β-oxidation) are depicted with star bursts. Metabolic routes (1–16) possibly associated with LD synthesis and β-oxidation are designated with red and blue arrows, respectively. Other routes are shown in black arrows. The abbreviations used are as follows: LDs = lipid droplets; ER = endoplasmic reticulum; HIFs = hypoxia inducible factors; ARNT = arylhydrocarbon receptor nuclear translocator; Ac-CoA = acetyl coenzyme A; LCFAs = long chain fatty acids; FABPs = fatty acid binding proteins; PPARs = peroxisome proliferator-activated receptors; LXRs = liver X receptors; SREBPs = sterol regulatory element binding proteins; RXR = retinoid X receptor; FASN = fatty acid synthase; SCD-1 = stearoyl CoA desaturase-1; LDL-R = low-density lipoprotein receptor; EVs = extracellular vesicles. The symbols used are as follows: : LCFAs, : cholesterol, : transporter, : receptor.

Mentions: Unlike normal cells, which mainly generate energy (adenosine triphosphate: ATP) through mitochondrial oxidative phosphorylation, cancer cells mainly use glycolysis to generate ATP even under sufficiently oxygenated conditions (aerobic glycolysis, also known as the “Warburg effect”) [1]. Cancer tissues can be exposed to hypoxia because of aberrant tumor vascularization, which induces the transcription of hypoxia inducible factors (HIFs) including HIF-1α and HIF-2α [2,3]. This leads to favorable conditions for this characteristic metabolism [1]. HIF-1α binds arylhydrocarbon receptor nuclear translocator (ARNT) and activates not only genes that promote glucose consumption, such as the glucose transporter solute carrier family 2 member 1 (SLC2A1, also known as GLUT1) [4] and hexokinase 2 (HK2) [1], but also genes involved in oxidative phosphorylation such as pyruvate dehydrogenase kinase 1 (PDK1) [1]. Increased levels of the PDK1 protein inhibit pyruvate dehydrogenase (pyruvate dehydrogenase phosphatase catalytic subunit 1 (PDP1, also known as PDH)) gene activity [1]. This inhibitory process leads to the suppression of acetyl-CoA production required for mitochondrial ATP production and de novo synthesis of lipids in the cytosol [4,5], thereby promoting cytosolic glycolysis to facilitate lactate secretion (Figure 1, route 1). Glutamine is another important energy source for cancer cells when glucose availability is limited [4,5] (Figure 1, route 2).


Lipid Droplets: A Key Cellular Organelle Associated with Cancer Cell Survival under Normoxia and Hypoxia
Schematic of the possible metabolic routes associated with lipid droplet (LD) synthesis in cancer cells exposed to normoxic conditions. Under normoxia, cancer cells are expected to have easy access to serum components. Such factors (O2, glucose, glutamine, and lipids) are designated by a larger font size compared with that of lactate. Major metabolic energy sources (glycolysis and β-oxidation) are depicted with star bursts. Metabolic routes (1–16) possibly associated with LD synthesis and β-oxidation are designated with red and blue arrows, respectively. Other routes are shown in black arrows. The abbreviations used are as follows: LDs = lipid droplets; ER = endoplasmic reticulum; HIFs = hypoxia inducible factors; ARNT = arylhydrocarbon receptor nuclear translocator; Ac-CoA = acetyl coenzyme A; LCFAs = long chain fatty acids; FABPs = fatty acid binding proteins; PPARs = peroxisome proliferator-activated receptors; LXRs = liver X receptors; SREBPs = sterol regulatory element binding proteins; RXR = retinoid X receptor; FASN = fatty acid synthase; SCD-1 = stearoyl CoA desaturase-1; LDL-R = low-density lipoprotein receptor; EVs = extracellular vesicles. The symbols used are as follows: : LCFAs, : cholesterol, : transporter, : receptor.
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Related In: Results  -  Collection

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ijms-17-01430-f001: Schematic of the possible metabolic routes associated with lipid droplet (LD) synthesis in cancer cells exposed to normoxic conditions. Under normoxia, cancer cells are expected to have easy access to serum components. Such factors (O2, glucose, glutamine, and lipids) are designated by a larger font size compared with that of lactate. Major metabolic energy sources (glycolysis and β-oxidation) are depicted with star bursts. Metabolic routes (1–16) possibly associated with LD synthesis and β-oxidation are designated with red and blue arrows, respectively. Other routes are shown in black arrows. The abbreviations used are as follows: LDs = lipid droplets; ER = endoplasmic reticulum; HIFs = hypoxia inducible factors; ARNT = arylhydrocarbon receptor nuclear translocator; Ac-CoA = acetyl coenzyme A; LCFAs = long chain fatty acids; FABPs = fatty acid binding proteins; PPARs = peroxisome proliferator-activated receptors; LXRs = liver X receptors; SREBPs = sterol regulatory element binding proteins; RXR = retinoid X receptor; FASN = fatty acid synthase; SCD-1 = stearoyl CoA desaturase-1; LDL-R = low-density lipoprotein receptor; EVs = extracellular vesicles. The symbols used are as follows: : LCFAs, : cholesterol, : transporter, : receptor.
Mentions: Unlike normal cells, which mainly generate energy (adenosine triphosphate: ATP) through mitochondrial oxidative phosphorylation, cancer cells mainly use glycolysis to generate ATP even under sufficiently oxygenated conditions (aerobic glycolysis, also known as the “Warburg effect”) [1]. Cancer tissues can be exposed to hypoxia because of aberrant tumor vascularization, which induces the transcription of hypoxia inducible factors (HIFs) including HIF-1α and HIF-2α [2,3]. This leads to favorable conditions for this characteristic metabolism [1]. HIF-1α binds arylhydrocarbon receptor nuclear translocator (ARNT) and activates not only genes that promote glucose consumption, such as the glucose transporter solute carrier family 2 member 1 (SLC2A1, also known as GLUT1) [4] and hexokinase 2 (HK2) [1], but also genes involved in oxidative phosphorylation such as pyruvate dehydrogenase kinase 1 (PDK1) [1]. Increased levels of the PDK1 protein inhibit pyruvate dehydrogenase (pyruvate dehydrogenase phosphatase catalytic subunit 1 (PDP1, also known as PDH)) gene activity [1]. This inhibitory process leads to the suppression of acetyl-CoA production required for mitochondrial ATP production and de novo synthesis of lipids in the cytosol [4,5], thereby promoting cytosolic glycolysis to facilitate lactate secretion (Figure 1, route 1). Glutamine is another important energy source for cancer cells when glucose availability is limited [4,5] (Figure 1, route 2).

View Article: PubMed Central - PubMed

ABSTRACT

The Warburg effect describes the phenomenon by which cancer cells obtain energy from glycolysis even under normoxic (O2-sufficient) conditions. Tumor tissues are generally exposed to hypoxia owing to inefficient and aberrant vasculature. Cancer cells have multiple molecular mechanisms to adapt to such stress conditions by reprogramming the cellular metabolism. Hypoxia-inducible factors are major transcription factors induced in cancer cells in response to hypoxia that contribute to the metabolic changes. In addition, cancer cells within hypoxic tumor areas have reduced access to serum components such as nutrients and lipids. However, the effect of such serum factor deprivation on cancer cell biology in the context of tumor hypoxia is not fully understood. Cancer cells are lipid-rich under normoxia and hypoxia, leading to the increased generation of a cellular organelle, the lipid droplet (LD). In recent years, the LD-mediated stress response mechanisms of cancer cells have been revealed. This review focuses on the production and functions of LDs in various types of cancer cells in relation to the associated cellular environment factors including tissue oxygenation status and metabolic mechanisms. This information will contribute to the current understanding of how cancer cells adapt to diverse tumor environments to promote their survival.

No MeSH data available.


Related in: MedlinePlus