Dropping in on lipid droplets: insights into cellular stress and cancer

Abstract

Lipid droplets (LD) have increasingly become a major topic of research in recent years following its establishment as a highly dynamic organelle. Contrary to the initial view of LDs being passive cytoplasmic structures for lipid storage, studies have provided support on how they act in concert with different organelles to exert functions in various cellular processes. Although lipid dysregulation resulting from aberrant LD homeostasis has been well characterised, how this translates and contributes to cancer progression is poorly understood. This review summarises the different paradigms on how LDs function in the regulation of cellular stress as a contributing factor to cancer progression. Mechanisms employed by a broad range of cancer cell types in differentially utilising LDs for tumourigenesis will also be highlighted. Finally, we discuss the potential of targeting LDs in the context of cancer therapeutics.

Keywords: cancer progression; cell stress; chemoresistance; lipid droplets.

Figure 1. Lipid droplet biogenesis

The neutral lipids, TG and cholesterol ester, are synthesised by ER membrane proteins. These lipid molecules then coalesce to form the core of a lens-shaped structure that protrudes towards the cytoplasm. The nascent LD buds off from the ER membrane to form the mature cytoplasmic organelle. Abbreviations: ATGL, adipose triglyceride lipase; DG, diacylglycerol; DGAT, diacylglycerol acyl-transferase; FA-CoA, fatty acyl-CoA; HSL, hormone-sensitive lipase; MG, monoacylglycerol; MGAT, monoacylglycerol acyl-transferase; MGL, monoacylglycerol lipase; PA, phosphatidic acid; PAP, phosphatidic acid phosphatase; PL, phospholipids.

Figure 2. Fundamental activation mechanism of major cellular stress responses

(Left panel) The UPR is activated by ER stress conditions (i.e. ER membrane perturbation and aberrant protein folding within the ER lumen). These stressors are affected by three distinct axes, namely Ire1α, PERK and ATF6. The cognate transcription factors, Xbp1, ATF4 and ATF6(N), then translocate into the nucleus to modulate gene expression including those of ER luminal chaperones and ERAD components. UPR activation concurrently attenuates global protein translation and induces LD formation to restore homeostasis. (Middle panel) Oxidative stressors in the form of reactive oxygen species are generated through energy metabolism. Accumulation of ROS potentially induces a cascade of events that damages DNA, proteins and long-chain PUFAs. This cellular threat is mitigated by the up-regulation of antioxidants that neutralise ROS. The failure to restore homeostasis under conditions of ER and oxidative stress ultimately results in apoptosis. (Right panel) In contrast with the UPR, the presence of misfolded proteins in the cytoplasm as well as elevated temperatures activates the heat shock response (HSR). Under these conditions, the monomeric HSF1 sensor forms the homotrimeric HSF1 transcription factor that translocates into the nucleus to increase expression of cytoplasmic protein chaperones to subsequently aid in the refolding and processing of misfolded client substrates. Abbreviations: ERAD, ER-associated degradation; PUFA: polysaturated fatty acid; ROS, reactive oxygen species.

Figure 3. Overview on the role of LDs in regulating cancer progression

Tumour cells import FFAs from the extracellular space and adipocyte. Subsequently, these can be stored into LDs to prevent the accumulation of ROS or degraded through β-oxidation to promote tumour growth and metastasis. LD accumulation is also triggered from ER stress to alleviate stress. In dendritic cells (DCs), accumulation of LDs dysregulates antigen presentation of tumour-associated antigens which may inhibit immune response. In parallel, LD-localised prostaglandin E₂ (PGE₂) might be secreted causing immunosuppression. In tumour cells, PGE₂ promotes cell proliferation and cell survival. COX-2, cyclooxygenase-2.