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Review
. 2018 Aug 26;19(9):2527.
doi: 10.3390/ijms19092527.

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

Victor García-González  1 , José Fernando Díaz-Villanueva  2 , Octavio Galindo-Hernández  3 , Israel Martínez-Navarro  4 , Gustavo Hurtado-Ureta  5 , Abril Alicia Pérez-Arias  6
Affiliations
Review

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

Victor García-González et al. Int J Mol Sci. .

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.

Keywords: breast cancer; ceramides; meta-inflammation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Metabolic implications associated to ceramide synthesis. Free fatty acid (FFA) such as palmitic acid is internalized through CD36, and ceramide synthesis is stimulated by serin-palmitoyl acyltransferase (SPT) through the addition of serine to produce sphinganine. Then, is converted into dihydroceramide by CerS and finally to ceramide by Des. Ceramides promote inhibition of Akt/PKB signaling by PKC function. Ceramides can be turned to GM3 which inhibits INRS, blocking insulin signaling. GM3 accumulation promotes the dissociation of IR/Cav-1 complex. Likewise, palmitic acid can function as a ligand for TLR-4, activating its signaling cascade that leads to the expression of genes encoding enzymes such as SPT, CerS, and Des. On the other hand, palmitic acid can be metabolized to DAG, which stimulates PKCε, activated PKCε phosphorylates Thr 1160 of INSR, causing its inhibition. Finally, ceramides could activate NLRP3 and lead to apoptosis by Caspase-1-dependent pathway. Image adapted from references: [9,10,11,12,13].
Figure 2
Figure 2
Overview of endoplasmic reticulum (ER) and mitochondria interactions. ER stress phenomenon promotes the activation of the de novo ceramide pathway, producing an increase in the exportation of dyhidrosphingosine and enzymes such as CerS1 and CerS6 through mitochondria-associated ER membranes (MAMs) or multivesicular endosomes (MEVs) to mitochondria (1), this originates the cleavage of Sig1R/Bip complex, Sig1R binds to IP3R3/VDCA-1 allowing the flow of Ca2+ through the ER to the inter-membranal space of the mitochondria by MCU (2), it can cross the inner mitochondrial membrane, producing a supersaturation in the mitochondrial matrix. This condition facilitates the activation of apoptosis by means of CHOP-dependent EROSα (3). In inter-membrane space, C16 ceramide leads to synthesis and assembly of pores that synergistically with Bax are translocated to OMM (4), this modifies the permeability of the membrane and allows the output of cytochrome C and proteins as SMAC/DIABLO and Omi/Htra (5). Later, cytochrome-C is associated with Apaf-1, promoting the change from procaspase-9 to caspase-9, leading to apoptosome formation. The complex Bad/Bim inhibits the antiapoptotic action of Bcl-2 and Bcl-xL, which in turn are associated with preventing the oligomerization of Bax with the pores, as well as inhibition of cytochrome C release (6). Image adapted from references: [4,14,18,37,38,39].
Figure 3
Figure 3
Schematic view of sphingolipid role in breast cancer progression. Structurally, the mammary ducts are composed of basal membrane, a layer of myoepithelial cells and another of luminal ductal cells. In the normal mammary epithelium, ceramides negatively regulate the Rb and CDK2 proteins, inhibiting cell proliferation. In carcinoma in situ, luminal tumor cells present an abnormal metabolism of ceramides, where sphingosine-1-phosphate (S1P) through S1PR promotes activation of the PI3K/Akt and MAPK pathways, inducing cell proliferation. The loss and/or degradation of the basement membrane allow the tumoral cells to migrate and invade the surrounding tissue. In this stage, S1PR promotes GTPases activation such as Rho and CDC42, inducing tumor invasion and consequently, metastasis. Image adapted from references: [12,19,92,102].
Figure 4
Figure 4
Ceramides and sphingolipids in breast cancer progression. S1P is a critical molecule involved in the modulation of angiogenesis. In endothelial cells, it has been demonstrated that S1P promotes proliferation, migration, and chemotaxis, resulting in the generation of intra-tumoral blood vessels that facilitate the process of metastasis. Moreover, S1P induces migration and invasion of breast cancer cells, promoting the process of tumor intravasation. Finally, in tumor cells, the SMase enzyme shows high activity, promoting the biogenesis and secretion of exosomes, extracellular vesicles that modulate angiogenesis, metastasis, and resistance to chemotherapy. Image adapted from references: [14,120,132,136].
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