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

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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 LD synthesis in cancer cells exposed to O2-deficient conditions. Under hypoxia, cancer cells are expected to have restricted access to serum components. Cancer cells are also expected to secrete high levels of lactate under hypoxia. Serum components and lactate are designated with small and large font sizes, respectively. Under hypoxia, glycolysis and β-oxidation should be accelerated and suppressed, respectively. Accordingly, facilitated glycolysis and inactivated fatty acid oxidation are represented by large and small font sizes, respectively. Metabolic routes (1–19) possibly associated with LD synthesis and glycolysis are designated with red and blue arrows, respectively. Other routes are shown in black arrows. The abbreviations used are as follows: CPT1 = carnitine palmitoyltransferase 1; HIG2 = hypoxia inducible protein 2; TAG = triacylglycerol. The symbol “?” is indicative of potential contribution in cancer cells.
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ijms-17-01430-f002: Schematic of the possible metabolic routes associated with LD synthesis in cancer cells exposed to O2-deficient conditions. Under hypoxia, cancer cells are expected to have restricted access to serum components. Cancer cells are also expected to secrete high levels of lactate under hypoxia. Serum components and lactate are designated with small and large font sizes, respectively. Under hypoxia, glycolysis and β-oxidation should be accelerated and suppressed, respectively. Accordingly, facilitated glycolysis and inactivated fatty acid oxidation are represented by large and small font sizes, respectively. Metabolic routes (1–19) possibly associated with LD synthesis and glycolysis are designated with red and blue arrows, respectively. Other routes are shown in black arrows. The abbreviations used are as follows: CPT1 = carnitine palmitoyltransferase 1; HIG2 = hypoxia inducible protein 2; TAG = triacylglycerol. The symbol “?” is indicative of potential contribution in cancer cells.

Mentions: Cholesterol uptake by RCC cells can be enhanced by the upregulation of low-density lipoprotein receptor (LDL-R) (Figure 1), resulting in the accumulation of LDs [49] via endosomal cholesterol trafficking (Figure 1, route 14). RNA interference experiments revealed that this LDL-R upregulation is HIF-1α dependent. The formation of LDs mediated by increased cholesterol uptake contributes to the RCC phenotype [49]. Hypoxia-inducible protein 2 (HIG2) is highly expressed in RCC tissues and cells even under normoxic culture conditions [50] (Figure 2). The HILPDA gene encoding HIG2 is a target gene of HIF-1α [50]. HIG2 is an LD protein that plays an important role in LD production [51]. HIG2 expression levels and patterns in RCC tissues are consistent with those of HIF-1α, implying that the HIF-1α–HIG2 pathway is significant for LD production in RCC cells. The perilipin 2 protein is another example of a HIF-driven LD protein associated with RCC [52]. HIF-2α is responsible for the induction of the PLIN2 gene, which encodes perilipin 2 and contributes to high LD synthesis in RCC cells.


Lipid Droplets: A Key Cellular Organelle Associated with Cancer Cell Survival under Normoxia and Hypoxia
Schematic of the possible metabolic routes associated with LD synthesis in cancer cells exposed to O2-deficient conditions. Under hypoxia, cancer cells are expected to have restricted access to serum components. Cancer cells are also expected to secrete high levels of lactate under hypoxia. Serum components and lactate are designated with small and large font sizes, respectively. Under hypoxia, glycolysis and β-oxidation should be accelerated and suppressed, respectively. Accordingly, facilitated glycolysis and inactivated fatty acid oxidation are represented by large and small font sizes, respectively. Metabolic routes (1–19) possibly associated with LD synthesis and glycolysis are designated with red and blue arrows, respectively. Other routes are shown in black arrows. The abbreviations used are as follows: CPT1 = carnitine palmitoyltransferase 1; HIG2 = hypoxia inducible protein 2; TAG = triacylglycerol. The symbol “?” is indicative of potential contribution in cancer cells.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5037709&req=5

ijms-17-01430-f002: Schematic of the possible metabolic routes associated with LD synthesis in cancer cells exposed to O2-deficient conditions. Under hypoxia, cancer cells are expected to have restricted access to serum components. Cancer cells are also expected to secrete high levels of lactate under hypoxia. Serum components and lactate are designated with small and large font sizes, respectively. Under hypoxia, glycolysis and β-oxidation should be accelerated and suppressed, respectively. Accordingly, facilitated glycolysis and inactivated fatty acid oxidation are represented by large and small font sizes, respectively. Metabolic routes (1–19) possibly associated with LD synthesis and glycolysis are designated with red and blue arrows, respectively. Other routes are shown in black arrows. The abbreviations used are as follows: CPT1 = carnitine palmitoyltransferase 1; HIG2 = hypoxia inducible protein 2; TAG = triacylglycerol. The symbol “?” is indicative of potential contribution in cancer cells.
Mentions: Cholesterol uptake by RCC cells can be enhanced by the upregulation of low-density lipoprotein receptor (LDL-R) (Figure 1), resulting in the accumulation of LDs [49] via endosomal cholesterol trafficking (Figure 1, route 14). RNA interference experiments revealed that this LDL-R upregulation is HIF-1α dependent. The formation of LDs mediated by increased cholesterol uptake contributes to the RCC phenotype [49]. Hypoxia-inducible protein 2 (HIG2) is highly expressed in RCC tissues and cells even under normoxic culture conditions [50] (Figure 2). The HILPDA gene encoding HIG2 is a target gene of HIF-1α [50]. HIG2 is an LD protein that plays an important role in LD production [51]. HIG2 expression levels and patterns in RCC tissues are consistent with those of HIF-1α, implying that the HIF-1α–HIG2 pathway is significant for LD production in RCC cells. The perilipin 2 protein is another example of a HIF-driven LD protein associated with RCC [52]. HIF-2α is responsible for the induction of the PLIN2 gene, which encodes perilipin 2 and contributes to high LD synthesis in RCC cells.

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