A role for caspase‐2 in sphingosine kinase 1 proteolysis in response to doxorubicin in breast cancer cells – implications for the <scp>CHK</scp>1‐suppressed pathway

Carroll, Brittany L.; Bonica, Joseph; Shamseddine, A.; Hannun, Yusuf A.; Obeid, Lina M.

doi:10.1002/2211-5463.12344

Cited by 18 publications

(18 citation statements)

References 44 publications

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“…In the triple-negative breast cancer cells with mutated p53, caspase-2 was not activated by doxorubicin treatment, and SPHK1 activity was preserved. However, suppression of the CHK1 was able to activate both caspase-2 and SPHK1 degradation (Carroll, Bonica, Shamseddine, Hannun, & Obeid, 2018). …”

Section: P53 and Ceramide Pathwaysmentioning

confidence: 99%

Ceramide Signaling and p53 Pathways

Jeffries¹,

Krupenko

2018

Advances in Cancer Research

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Ceramides, important players in signal transduction, interact with multiple cellular pathways, including p53 pathways. However, the relationship between ceramide and p53 is very complex, and mechanisms underlying their coregulation are diverse and not fully characterized. The role of p53, an important cellular regulator and a transcription factor, is linked to its tumor suppressor function. Ceramides are involved in the regulation of fundamental processes in cancer cells including cell death, proliferation, autophagy, and drug resistance. This regulation, however, can be pro-death or pro-survival depending on cancer type, the balance between ceramide species, the rate of their synthesis and utilization, and the availability of a specific array of downstream targets. This chapter highlights the central role of ceramide in sphingolipid metabolism, its role in cancer, specific effectors in ceramide pathways controlled by p53, and coregulation of ceramide and p53 signaling. We discuss the recent studies, which underscore the function of p53 in the regulation of ceramide pathways and the reciprocal regulation of p53 by ceramide. This complex relationship is based on several molecular mechanisms including the p53-dependent transcriptional regulation of enzymes in sphingolipid pathways, the activation of mutant p53 through ceramide-mediated alternative splicing, as well as modulation of the p53 function through direct and indirect effects on p53 coregulators and downstream targets. Further insight into the connections between ceramide and p53 will allow simultaneous targeting of the two pathways with a potential to yield more efficient anticancer therapeutics.

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Section: P53 and Ceramide Pathwaysmentioning

confidence: 99%

Ceramide Signaling and p53 Pathways

Jeffries¹,

Krupenko

2018

Advances in Cancer Research

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“…31 At doses as low as 4 nM, bortezomib was able to inhibit SK1 proteolysis 24 hours after the initiation of ser/gly starvation (Figure 1F). Caspase 2 and caspase 7 inhibitors, previously shown to inhibit p53-induced SK1 proteolysis in response to genotoxic drugs, 26,32,33 had no effect on ser/gly-starvationinduced SK1 proteolysis (Figure 1G), although both caspase inhibitors were able to protect SK1 from proteolysis induced by etoposide (Figure 1G, bottom), suggesting a previously unappreciated mechanism of controlling SK1 protein levels. In an attempt to ascertain the mechanism behind the downregulation of SK1, the role of Kelch-like protein 5 (KLHL5) was investigated.…”

Section: Serine Deprivation Causes the Downregulation Of Sk1 Proteinmentioning

confidence: 86%

Sphingosine kinase 1 downregulation is required for adaptation to serine deprivation

et al. 2021

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It has been well-established that cancer cells often display altered metabolic profiles, and recent work has concentrated on how cancer cells adapt to serine removal. Serine can be either taken exogenously or synthesized from glucose, and its regulation forms an important mechanism for nutrient integration. One of the several important metabolic roles for serine is in the generation of bioactive sphingolipids since it is the main substrate for serine palmitoyltransferase, the initial and rate-limiting enzyme in the synthesis of sphingolipids. Previously, serine deprivation has been connected to the action of the tumor suppressor p53, and we have previously published on a role for p53 regulating sphingosine kinase 1 (SK1), an enzyme that phosphorylates sphingosine to form sphingosine-1-phosphate (S1P). SK1 is a key enzyme in sphingolipid synthesis that functions in pro-survival and tumor-promoting pathways and whose expression is also often elevated in cancers. Here we show that SK1 was degraded during serine starvation in a time and dose-dependent manner, which led to sphingosine accumulation. This was independent of effects on p53 but required the action of the proteasome. Furthermore, we show that overexpression of SK1, to compensate for SK1 loss, was detrimental to cell growth under conditions of serine starvation, demonstrating that the suppression of SK1 under these conditions is adaptive.Mitochondrial oxygen consumption decreased in response to SK1 degradation, and this was accompanied by an increase in intracellular reactive oxygen species (ROS). Suppression of ROS with N-acteylcysteine resulted in suppression of the metabolic adaptations and in decreased cell growth under serine deprivation. The effects of SK1 suppression on ROS were mimicked by D-erythro-sphingosine, whereas S1P was ineffective, suggesting that the effects of loss of SK1 were due to the accumulation of its substrate sphingosine. This study reveals a new mechanism for regulating SK1 levels and a link of SK1 to serine starvation as well as mitochondrial function.

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“…Targeted drug-delivery can decrease unwanted damage to non-cancerous cells and make the most of the therapeutic responses of the drug. [3][4][5][6][7][8] Synthetic and biodegradable polymers have been extensively used as a carrier for drugs, genes, and molecular imaging agents. Poly[lactic-co(glycolic acid)], PLGA, is reputed for its biocompatibility, nontoxicity, favorable degradation kinetics, and more importantly, it is a FDA-approved carrier.…”

Section: Introductionmentioning

confidence: 99%