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

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.

Keywords: cancer; hypoxia; lipid droplets; normoxia; stress response.

Figure 1

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.

Figure 2

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.

Figure 3

Potential effect of LDs on the ER-stress condition in cancer cells caused by O₂ deficiency. Cancer cells sufficiently supplied with O₂ show proper protein folding processes in the ER, including disulfide bond formation in association with multiple enzymatic activities as depicted. However, these processes may be dysregulated under hypoxia, thereby leading to redox imbalance. Accumulated misfolded proteins result in the ER-stress condition with generation of ROS. LDs are expected to suppress this toxic condition. Perilipin2 contributes to the maintenance of ER homeostasis. HIG2 is another LD membrane protein; however, its effect on ER homeostasis during hypoxia is currently unclear. OGA and Cidec potentially contribute to ER homeostasis by promoting ERAD. Enhanced degradation of PPFs via ERAD potentially contributes to survival of cancer cells exposed to hypoxia. The abbreviations used are as follows: Nox4 = NADPH oxidase 4; PDI = protein disulfide isomerase; ERO1α = ER oxidase 1α; CEs = cholesterol esters; ROS = reactive oxygen species; OGA = protein-O-linked N-acetyl-β-glucosaminidase; CIDEs = cell death-inducing DFF45-like effectors; ERAD = ER-associated degradation; PPFs = proteolytic protein fragments. The symbol “?” is indicative of potential contribution of HIG2. White, grey, and black bold arrows are indicative of transition from normoxia to hypoxia, protein degradation, and activation process, respectively.

Figure 4

Model of ICAM1 induction in ovarian cancer cells exposed to LCFA deficiency and hypoxia (left schematic). Expression of the ICAM1 gene is robustly enhanced (a bold red bent arrow) under this stress condition, leading to high ICAM-1 expression on the cell surface (a black bold arrow). ER stress is also induced in cancer cells; however, it is not responsible for this transcriptional activation. In contrast, ICAM1 expression is relatively low in cancer cells exposed to normoxia (right schematic). The LD level in these cells is relatively high owing to a sufficient LCFA supply.