Adding fuel to the fire: The lipid droplet and its associated proteins in cancer progression

Abstract

A lipid droplet (LD) is an organelle that consists of a phospholipid monolayer and a neutral lipid core, with proteins embedded in or attached to its surface. Until recently, cancers had long been regarded as genetic disorders with the abnormal activation of oncogenes and inactivation of tumor suppressor genes before their quality of a metabolic disorder began to be recognized. The last decade has witnessed the recognition of several metabolic characteristics of cancer cells, among which one is the accumulation of lipid droplets; therefore, attention has been given to exploring the role of LDs in carcinomas. In addition, there has been a remarkable expansion in understanding the complexity of LD's function in cellular homeostasis, including but not limited to energy supply, endoplasmic reticulum (ER) stress and oxidative stress management, or lipotoxicity alleviation. Thus, lipid droplet-associated proteins, which to a great extent determine the dynamics of a lipid droplet, have attracted the interest of numerous cancer researchers and their potential as cancer diagnostic biomarkers and therapeutic targets has been affirmed by emerging evidence. In this review, we systematically summarize the critical role of LDs in cancer and then focus on four categories of lipid droplet-associated proteins having the most direct influence on LD biosynthesis (diacylglycerol acyltransferase 1 (DGAT1) and diacylglycerol acyltransferase 2 (DGAT2)), degradation (adipose triglyceride lipase (ATGL)), and two renowned protein families on the LD surface (perilipins and cell death-inducing DNA fragmentation factor alpha-like effectors (CIDEs)). In this way, we aim to highlight their important role in tumor progression and their potential in clinical applications.

Lipid droplets provide metabolic flexibility for cancer progression

“…In mammalian cells, PLINs play a vital role not only in LD biogenesis [151,152] but also in regulating lipolysis and lipophagy [153][154][155]. In contrast to PLIN-1, 4, and 5 that are expressed in specific tissues, PLIN-2 and PLIN-3 are more ubiquitous [156]. The expression of PLIN-2 is understood as an indicator of the cellular LD content in healthy and cancer cells [49,156].…”

“…In contrast to PLIN-1, 4, and 5 that are expressed in specific tissues, PLIN-2 and PLIN-3 are more ubiquitous [156]. The expression of PLIN-2 is understood as an indicator of the cellular LD content in healthy and cancer cells [49,156]. Next, we will explore the implication of PLIN-2 in cancer progression, while the levels and implications of PLIN-3, 4, and 5 are summarized in Table 1.…”

LncRNAs‐circRNAs as Rising Epigenetic Binary Superstars in Regulating Lipid Metabolic Reprogramming of Cancers

“…[69,70] For instance, ATGL can promote proliferation and invasiveness in prostate, lung and colorectal cancer cells, but acts as a suppressor of malignancy in other types of cancers. [70,71] More interestingly, breast cancer cells can obtain free fatty acids to promote autologous proliferation and migration via ATGL-dependent lipolysis in both itself and adipocytes in the local environment. [72]…”

“…[ 157 ] Additionally, esterification of fatty acid and cholesterol usually contribute the formation of lipid droplets (LDs) for energy storage, ROS homeostasis and entrapment of anticancer drugs in cancer cells. [ 71 ] The lipid‐metabolic related lncRNAs and circRNAs in cancer have been identified to modulate the metabolism of LDs in cancer. For example, linc01410 was overexpressed in cervical cancer to release miR‐532‐5p‐mediated repression of PLIN2, ACC1 and FASN expression, which promoted LDs formation and metastasis of cervical cancer cells.…”

The lipid droplet in cancer: From being a tumor‐supporting hallmark to clinical therapy

“…Generally, LDs act as double‐edged swords in normal and pathological settings. In normal cells, three fatty acids (FAs) are linked to glycerol, esterified into neutral lipids, and stored in LDs to avoid lipid toxicity caused by excessive free fatty acid (FFA) accumulation 4 . Due to the high dynamic abundance of intracellular FAs, neutral lipids in LDs are reactivated and released into the cytoplasm 5 .…”