Sphingolipid/Ceramide Pathways and Autophagy in the Onset and Progression of Melanoma: Novel Therapeutic Targets and Opportunities

Lai, Michele; Rocca, Veronica La; Amato, Rachele; Freer, Giulia; Pistello, Mauro

doi:10.3390/ijms20143436

Cited by 34 publications

(32 citation statements)

References 102 publications

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“…Autophagy is a major pathway involved in survival during starvation and plays a key role in chemotherapy resistance [ 25 ]. To evaluate the possible contribution of AC to autophagy, we measured autophagy-related protein levels in A375 AC-null cells, which harbour two frameshift mutations in both AC alleles [ 16 ].…”

Section: Resultsmentioning

confidence: 99%

“…In LSDs, a significant number of autophagosomes remains in the cytosol, suggesting incomplete autophagy [ 32 ]. Therefore, autophagy impairment observed in LSDs might depend on the last phase of autophagy, in which autophagosomes are targeted by lysosomes to form autolysosomes [ 25 ]. Consistently with these observations, our data show that autophagy is impaired also in A375 AC-null cells, where LC3 isoform II is decreased, but is restored after the transfection of AC in trans.…”

Section: Discussionmentioning

confidence: 99%

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Ablation of Acid Ceramidase Impairs Autophagy and Mitochondria Activity in Melanoma Cells

Lai

Rocca

Amato

et al. 2021

IJMS

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Cutaneous melanoma is often resistant to therapy due to its high plasticity, as well as its ability to metabolise chemotherapeutic drugs. Sphingolipid signalling plays a pivotal role in its progression and metastasis. One of the ways melanoma alters sphingolipid rheostat is via over-expression of lysosomal acid ceramidase (AC), which catalyses the hydrolysis of pro-apoptotic long-chain ceramides into sphingosine and fatty acid. In this report, we examine the role of acid ceramidase in maintaining cellular homeostasis through the regulation of autophagy and mitochondrial activity in melanoma cell lines. We show that under baseline conditions, wild-type melanoma cells had 3-fold higher levels of the autophagy marker, microtubule-associated proteins 1A/1B light chain 3B (LC3 II), compared to AC-null cells. This difference was further magnified after cell starvation. Moreover, we noticed autophagy impairment in A375 AC-null cells, possibly due to local accumulation of non-metabolized ceramides. Nonetheless, we observed that AC-null cells exhibited a significant increase in mitochondrial membrane potential compared to control cells. Consistent with this observation, we found that, after total starvation, ~30% of AC-null cells undergo apoptosis compared to ~6% of wild-type cells. As expected, AC transfection restored viability in A375 AC-null cells. Together, these findings suggest that AC-null melanoma cells change and adapt their metabolism to survive in the absence of AC, although in a way that does not allow them to cope with the stress of nutrient deprivation.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ablation of Acid Ceramidase Impairs Autophagy and Mitochondria Activity in Melanoma Cells

Lai

Rocca

Amato

et al. 2021

IJMS

Self Cite

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“…However, several enzymes (e.g., acid ceramidase, ceramide kinase, etc.) that accelerate the metabolism of ceramides, have been found to have an enhanced expression level in multiple tumors (67,68,70). Therefore, ceramide metabolism has been utilized to develop some drugs that target these vital enzymes thus inducing lethal ceramide accumulation and overcoming cancer therapy resistance (67).…”

Section: Sphingolipid Metabolism Involves In Regulating Tumor Prolifementioning

confidence: 99%

The Lipid Metabolic Landscape of Cancers and New Therapeutic Perspectives

et al. 2020

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Lipid metabolism reprograming, as a hallmark of malignancy, has received renewed interest in recent years in such areas as energy sources, cell membrane components, and signaling molecules involved in the rapid tumor growth and the adaptation to the tumor microenvironment. Lipid metabolism deregulation in cancer involves multiple aspects, including an increased lipid uptake, endogenous de novo fatty acid synthesis, fatty acid oxidation, and cholesterol accumulation, thereby promoting tumor growth and progression. Recent advances in the understanding of specific metabolic alterations in cancer reveal novel pathogenesis mechanisms and a growing number of drugs targeting lipid metabolism have been applied in anti-tumor therapy. Thus, this review discusses the lipid metabolic landscape of cancers and the interplay with oncogenic signaling, and summarizes potential therapeutic targets to improve the therapeutic efficiency in cancer patients, in order to provide more reference and thinking for the treatment of lipid metabolism of cancer patients.

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“…In general, autophagy has been widely considered as a tumor suppressor mechanism at the stage of carcinogenesis, while tumor-promoting role of autophagy has been associated with progression of cancer, including melanoma [55,[64][65][66]. It has been demonstrated that autophagy suppressed melanomagenesis by promoting senescence, and decreased expression of ATG5 was sufficient to preclude this process [67].…”

Section: Autophagy In Melanomamentioning

confidence: 99%

Non-Apoptotic Cell Death Signaling Pathways in Melanoma

Hartman

2020

IJMS

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Resisting cell death is a hallmark of cancer. Disturbances in the execution of cell death programs promote carcinogenesis and survival of cancer cells under unfavorable conditions, including exposition to anti-cancer therapies. Specific modalities of regulated cell death (RCD) have been classified based on different criteria, including morphological features, biochemical alterations and immunological consequences. Although melanoma cells are broadly equipped with the anti-apoptotic machinery and recurrent genetic alterations in the components of the RAS/RAF/MEK/ERK signaling markedly contribute to the pro-survival phenotype of melanoma, the roles of autophagy-dependent cell death, necroptosis, ferroptosis, pyroptosis, and parthanatos have recently gained great interest. These signaling cascades are involved in melanoma cell response and resistance to the therapeutics used in the clinic, including inhibitors of BRAF mut and MEK1/2, and immunotherapy. In addition, the relationships between sensitivity to non-apoptotic cell death routes and specific cell phenotypes have been demonstrated, suggesting that plasticity of melanoma cells can be exploited to modulate response of these cells to different cell death stimuli. In this review, the current knowledge on the non-apoptotic cell death signaling pathways in melanoma cell biology and response to anti-cancer drugs has been discussed.

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Sphingolipid/Ceramide Pathways and Autophagy in the Onset and Progression of Melanoma: Novel Therapeutic Targets and Opportunities

Cited by 34 publications

References 102 publications

Ablation of Acid Ceramidase Impairs Autophagy and Mitochondria Activity in Melanoma Cells

Ablation of Acid Ceramidase Impairs Autophagy and Mitochondria Activity in Melanoma Cells

The Lipid Metabolic Landscape of Cancers and New Therapeutic Perspectives

Non-Apoptotic Cell Death Signaling Pathways in Melanoma

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