Ceramide Metabolism Balance, a Multifaceted Factor in Critical Steps of Breast Cancer Development

Abstract

Ceramides are key lipids in energetic-metabolic pathways and signaling cascades, modulating critical physiological functions in cells. While synthesis of ceramides is performed in endoplasmic reticulum (ER), which is altered under overnutrition conditions, proteins associated with ceramide metabolism are located on membrane arrangement of mitochondria and ER (MAMs). However, ceramide accumulation in meta-inflammation, condition that associates obesity with a chronic low-grade inflammatory state, favors the deregulation of pathways such as insulin signaling, and induces structural rearrangements on mitochondrial membrane, modifying its permeability and altering the flux of ions and other molecules. Considering the wide biological processes in which sphingolipids are implicated, they have been associated with diseases that present abnormalities in their energetic metabolism, such as breast cancer. In this sense, sphingolipids could modulate various cell features, such as growth, proliferation, survival, senescence, and apoptosis in cancer progression; moreover, ceramide metabolism is associated to chemotherapy resistance, and regulation of metastasis. Cell–cell communication mediated by exosomes and lipoproteins has become relevant in the transport of several sphingolipids. Therefore, in this work we performed a comprehensive analysis of the state of the art about the multifaceted roles of ceramides, specifically the deregulation of ceramide metabolism pathways, being a key factor that could modulate neoplastic processes development. Under specific conditions, sphingolipids perform important functions in several cellular processes, and depending on the preponderant species and cellular and/or tissue status can inhibit or promote the development of metabolic and potentially breast cancer disease.

The Role of Ceramides in Insulin Resistance

“…Experimental data suggest that ceramide synthesis and degradation is associated with several crucial cellular responses (apoptosis, cell cycle, and autophagy) (33, 36, 45, 98). García-González and co-workers described an interrelationship between ceramide metabolism and cancer development and progression, highlighting its importance in the modulation of the pivotal processes such as apoptosis, proliferation, migration, invasion, and metastasis (122). Hence, it would be essential to verify whether the ceramide synthesis inhibitors used to prevent insulin resistance would not consequently lead to a carcinogenic effect.…”

Fatty Acid and Lipopolysaccharide Effect on Beta Cells Proteostasis and its Impact on Insulin Secretion

“…Interestingly, there is a mild increase of insulin release with PAO treatment with respect to controls. Data suggest that there is no metabolic effect that could modulate the treatment with unsaturated fatty acids, considering the quantification of triglycerides wherein only a slight increase in treatment of PA and LPS was registered, as well as the evaluation of targets such as serine palmitoyl-transferase (SPT), a key enzyme that uses palmitoyl-CoA and serine during ceramide synthesis (Figure 6D), which has been involved in several pathological diseases [38]. Then, our results suggest that under the cellular conditions evaluated, there was no significant metabolic alteration in β-cells.…”

Ceramide and Regulation of Vascular Tone

“…The evidence on the potential or actual involvement of ceramide metabolism in the etiopathogenesis of a growing number of conditions has been summarized and discussed in several very recent reviews and editorial comments. These conditions include, among others, cancer [10,127,128], neurological, neurodegenerative, and psychiatric disorders [7,15,57,129,130], infection/inflammation [131,132,133,134], metabolic conditions [135,136,137,138], cardiovascular disease [139,140,141,142], eye disease [143], skin disease [144,145], and lung disorders [4,14]. Although an exhaustive review is beyond the scope of this article, we will provide a brief description of the most relevant evidence from human studies on the role of ceramide in cardiovascular and pulmonary conditions.…”

“…Ceramide has a prominent role in the regulation of programmed cell death (apoptosis) induced by tumor necrosis factor alpha (TNF-α) or FAS ligand [9]. In addition to apoptosis, ceramide has been implicated in endothelial oxidative stress, growth inhibition, cytoskeleton changes, senescence, and vascular tone regulation [1,2,10,11,12,13,14,15]. Thus, ceramide and S1P are bioactive sphingolipids with opposite cell functions, which has led to the proposal of a ‘sphingolipid rheostat’, according to which the cell fate (death/survival) is determined by the balance between ceramide and S1P [2].…”