Fanning the Flames of Endoplasmic Reticulum (ER) Stress: Can Sphingolipid Metabolism Be Targeted to Enhance ER Stress-Associated Immunogenic Cell Death in Cancer?

Abstract

The three arms of the unfolded protein response (UPR) surveil the luminal environment of the endoplasmic reticulum (ER) and transmit information through the lipid bilayer to the cytoplasm to alert the cell of stress conditions within the ER lumen. That same lipid bilayer is the site of de novo synthesis of phospholipids and sphingolipids. Thus, it is no surprise that lipids are modulated by and are modulators of ER stress. Given that sphingolipids have both prosurvival and proapoptotic effects, they also exert opposing effects on life/death decisions in the face of prolonged ER stress detected by the UPR. In this review, we will focus on several recent studies that demonstrate how sphingolipids affect each arm of the UPR. We will also discuss the role of sphingolipids in the process of immunogenic cell death downstream of the protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiating factor 2α (eIF2α) arm of the UPR. Furthermore, we will discuss strategies to target the sphingolipid metabolic pathway that could potentially act synergistically with agents that induce ER stress as novel anticancer treatments. SIGNIFICANCE STATEMENT: This review provides the readers with a brief discussion of the sphingolipid metabolic pathway and the unfolded protein response. The primary focus of the review is the mechanism(s) by which sphingolipids modulate the endoplasmic reticulum (ER) stress response pathways and the critical role of sphingolipids in the process of immunogenic cell death associated with the ER stress response.

Fig. 1.

Cellular sphingolipid biosynthesis and breakdown. Metabolism of sphingolipids is compartmentalized and is catalyzed by numerous enzymes. Entry into the sphingolipid biosynthetic pathway initiates with the de novo synthesis pathway and terminates with the breakdown of sphingosine-1-phosphate by S1P lyase, which produces nonsphingolipid metabolites. Enzymes are depicted by rectangular boxes. CERT, ceramide transport protein; KDHR, 3-ketodihyrdosphingosine reductase; MDR1, multidrug resistance protein 1/p-glycoprotein; S1PL, S1P lyase; SMS, sphingomyelin synthase; SPT, serine palmitoyltransferase.

Fig. 2.

Strategies to induce Cer accumulation in cancer cells leading to enhanced ER stress and/or ICD. Cer levels within cancer cells can be increased by enhancing the production or inhibiting the breakdown (“detoxification”) of Cer. Agents/strategies to increase Cer production are denoted in green. Agents that inhibit Cer metabolism are denoted in red. Where appropriate, agents that are FDA approved for cancer or undergoing clinical trials for cancer are noted. The further development of highly potent acid ceramidase, ceramide kinase, and sphingosine kinase inhibitors is of the highest importance.