Ceramide Synthase 6 Maximizes p53 Function to Prevent Progeny Formation from Polyploid Giant Cancer Cells

Lü, Ping; White‐Gilbertson, Shai; Beeson, Gyda; Beeson, Craig C.; Öğretmen, Besim; Norris, James S.; Voelkel‐Johnson, Christina

doi:10.3390/cancers13092212

Cited by 19 publications

(9 citation statements)

References 40 publications

(47 reference statements)

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“…In agreement with our findings that tetraploid worms do not respire at higher rates than diploid worms, we did not see significant enrichment in genes related to mitochondrial function between diploid and tetraploid worms, or enrichment of other energy metabolism pathways such as glycolysis or fatty acid oxidation. We did see a trending significance of sphingolipid pathways, which have been previously implicated in polyploid cancer cells 31 . In contrast to studies in cancer cells, we observed no change or downregulation of the ceramides in our study (Supplemental Fig.…”

Section: Resultsmentioning

confidence: 48%

The consequences of tetraploidy on Caenorhabditis elegans physiology and sensitivity to chemotherapeutics

Misare,

Ampolini,

Gonzalez

et al. 2023

Sci Rep

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Polyploid cells contain more than two copies of each chromosome. Polyploidy has important roles in development, evolution, and tissue regeneration/repair, and can arise as a programmed polyploidization event or be triggered by stress. Cancer cells are often polyploid. C. elegans nematodes are typically diploid, but stressors such as heat shock and starvation can trigger the production of tetraploid offspring. In this study, we utilized a recently published protocol to generate stable tetraploid strains of C. elegans and compared their physiological traits and sensitivity to two DNA-damaging chemotherapeutic drugs, cisplatin and doxorubicin. As prior studies have shown, tetraploid worms are approximately 30% longer, shorter-lived, and have a smaller brood size than diploids. We investigated the reproductive defect further, determining that tetraploid worms have a shorter overall germline length, a higher rate of germ cell apoptosis, more aneuploidy in oocytes and offspring, and larger oocytes and embryos. We also found that tetraploid worms are modestly protected from growth delay from the chemotherapeutics but are similarly or more sensitive to reproductive toxicity. Transcriptomic analysis revealed differentially expressed pathways that may contribute to sensitivity to stress. This study reveals phenotypic consequences of whole-animal tetraploidy that make C. elegans an excellent model for ploidy differences.

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Section: Resultsmentioning

confidence: 48%

The consequences of tetraploidy on Caenorhabditis elegans physiology and sensitivity to chemotherapeutics

Misare,

Ampolini,

Gonzalez

et al. 2023

Sci Rep

Self Cite

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“…Recent studies have demonstrated that CerS6-derived C16-ceramide is crucial for maintaining the stability and enhancing the function of p53 [ 33 , 34 ]. Furthermore, a positive feedback loop of CerS6-derived C16-ceramide-p53 signaling was reported to be an important mechanism to maximize p53 function [ 35 ]. Exercise has been shown to activate p53 in some cancer types [ 36 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

Exercise Promotes Pro-Apoptotic Ceramide Signaling in a Mouse Melanoma Model

Lee

Savage

Maegawa

et al. 2022

Cancers

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Ceramides are essential sphingolipids that mediate cell death and survival. Low ceramide content in melanoma is one mechanism of drug resistance. Thus, increasing the ceramide content in tumor cells is likely to increase their sensitivity to cytotoxic therapy. Aerobic exercise has been shown to modulate ceramide metabolism in healthy tissue, but the relationship between exercise and ceramide in tumors has not been evaluated. Here, we demonstrate that aerobic exercise causes tumor cell apoptosis and accumulation of pro-apoptotic ceramides in B16F10 but not BP melanoma models using mice. B16F10 tumor-bearing mice were treated with two weeks of moderate treadmill exercise, or were control, unexercised mice. A reverse-phase protein array was used to identify canonical p53 apoptotic signaling as a key pathway upregulated by exercise, and we demonstrate increased apoptosis in tumors from exercised mice. Consistent with this finding, pro-apoptotic C16-ceramide, and the ceramide generating enzyme ceramide synthase 6 (CerS6), were higher in B16F10 tumors from exercised mice, while pro-survival sphingosine kinase 1 (Sphk1) was lower. These data suggest that exercise contributes to B16F10 tumor cell death, possibly by modulating ceramide metabolism toward a pro-apoptotic ceramide/sphingosine-1-phosphate balance. However, these results are not consistent in BP tumors, demonstrating that exercise can have different effects on tumors of different patient or mouse origin with the same diagnosis. This work indicates that exercise might be most effective as a therapeutic adjuvant with therapies that kill tumor cells in a ceramide-dependent manner.

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“…However, this inhibition can be prevented by inhibiting ASAH1 or by expressing functional P53. In contrast, P53 loss and low C16 ceramide levels, due to altered sphingolipid metabolism, promote PGCCs progeny formation 162 …”

Section: Reactivation Of Dormant Pgccs Promotes Tumour Invasion and M...mentioning

confidence: 97%

“…Driving recurrence and promote metastasis 162 Re-enter the cell cycle and initiate the metastasis 65 Microenvironmental signals…”

Section: Recurrence and Metastasismentioning

confidence: 99%

Dormant cancer cells and polyploid giant cancer cells: The roots of cancer recurrence and metastasis

Jiao,

Yu,

Zheng

et al. 2024

Clinical & Translational Med

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Tumour cell dormancy is critical for metastasis and resistance to chemoradiotherapy. Polyploid giant cancer cells (PGCCs) with giant or multiple nuclei and high DNA content have the properties of cancer stem cell and single PGCCs can individually generate tumours in immunodeficient mice. PGCCs represent a dormant form of cancer cells that survive harsh tumour conditions and contribute to tumour recurrence. Hypoxic mimics, chemotherapeutics, radiation and cytotoxic traditional Chinese medicines can induce PGCCs formation through endoreduplication and/or cell fusion. After incubation, dormant PGCCs can recover from the treatment and produce daughter cells with strong proliferative, migratory and invasive abilities via asymmetric cell division. Additionally, PGCCs can resist hypoxia or chemical stress and have a distinct protein signature that involves chromatin remodelling and cell cycle regulation. Dormant PGCCs form the cellular basis for therapeutic resistance, metastatic cascade and disease recurrence. This review summarises regulatory mechanisms governing dormant cancer cells entry and exit of dormancy, which may be used by PGCCs, and potential therapeutic strategies for targeting PGCCs.

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Ceramide Synthase 6 Maximizes p53 Function to Prevent Progeny Formation from Polyploid Giant Cancer Cells

Cited by 19 publications

References 40 publications

The consequences of tetraploidy on Caenorhabditis elegans physiology and sensitivity to chemotherapeutics

The consequences of tetraploidy on Caenorhabditis elegans physiology and sensitivity to chemotherapeutics

Exercise Promotes Pro-Apoptotic Ceramide Signaling in a Mouse Melanoma Model

Dormant cancer cells and polyploid giant cancer cells: The roots of cancer recurrence and metastasis

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