p53 and Ceramide as Collaborators in the Stress Response

Abstract

The sphingolipid ceramide mediates various cellular processes in response to several extracellular stimuli. Some genotoxic stresses are able to induce p53-dependent ceramide accumulation leading to cell death. However, in other cases, in the absence of the tumor suppressor protein p53, apoptosis proceeds partly due to the activity of this “tumor suppressor lipid”, ceramide. In the current review, we describe ceramide and its roles in signaling pathways such as cell cycle arrest, hypoxia, hyperoxia, cell death, and cancer. In a specific manner, we are elaborating on the role of ceramide in mitochondrial apoptotic cell death signaling. Furthermore, after highlighting the role and mechanism of action of p53 in apoptosis, we review the association of ceramide and p53 with respect to apoptosis. Strikingly, the hypothesis for a direct interaction between ceramide and p53 is less favored. Recent data suggest that ceramide can act either upstream or downstream of p53 protein through posttranscriptional regulation or through many potential mediators, respectively.

Mitochondrial retrograde signaling at the crossroads of tumor bioenergetics, genetics and epigenetics

“…It will be interesting to investigate potential crosstalk between the Cn mediated retrograde signaling reported by us and other reported retrograde signaling pathways such as ROS-induced TFGβ signaling, HIF1α, Ras, p53 signaling (Jain, Rivera et al 2013;Hage-Sleiman, Esmerian et al 2013). Identifying a convergence point of these various signaling modes will help in elucidating the global picture of mitochondrial retrograde signaling.…”

Potential Roles of Magnesium Deficiency in Inflammation and Atherogenesis: Importance and Cross-talk of Platelet-Activating Factor and Ceramide

“…It has been shown by our group [4,25,43,51] and others [52][53][54] that ceramides, in increased levels, found in the atherogenic process[mixed in plaques; unpublished findings ], at least in rabbits, and stimulated in MgD states could be important causal and initiating agents [16,17].…”

“…We have recently demonstrated that cerebral, aortic and coronary VSM cells can also elaborate and release PAF [69]. There are some reports that both PAF and ceramides may result in transformation of VSM cells from one phenotype to another, as is typical in the atherosclerotic process [53,54,72,73]. In addition, like we see in MgD, PAF produces vasoconstriction of blood vessels and a variety of VSM types [for recent review, see 69], as do several of the ceramides [69,74,75].…”

“…Ceramides are now thought to play important roles in fundamental processes such as inflammation, angiogenesis, membrane-receptor functions, cell proliferation, microcirculatory functions, cell adhesion, immunogenic responses, excitation-coupling events in smooth muscles, and cell death(i.e., apoptosis) [52][53][54][55][56][57]. SPT 1 and SPT 2 are the rate-limiting enzymes in the biosynthesis of sphingolipids [58].…”

Examining impacts of ceranib-2 on the proliferation, morphology and ultrastructure of human breast cancer cells

“…Inhibitors of ceramidases were reported to induce apoptosis and cause cell cycle arrest (Bhabak et al 2013). Therefore, pharmaceutical/preclinical research and later clinical trials of cancer cases may include ceramide and sphingolipids (Sleiman et al 2013) as well ceramidases. In the treatments with ceramidase inhibitors or exogenous ceramides cell cycle arrest and apoptosis are induced by increasing the ceramide concentration in the cells of breast (Sanger et al 2015) and prostate cancers (Beckham et al 2012).…”