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Review
. 2019 Jul 12;20(14):3436.
doi: 10.3390/ijms20143436.

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

Michele Lai  1 , Veronica La Rocca  1 , Rachele Amato  1 , Giulia Freer  1 , Mauro Pistello  2   3
Affiliations
Review

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

Michele Lai et al. Int J Mol Sci. .

Abstract

Melanoma is a malignant tumor deriving from neoplastic transformation of melanocytes. The incidence of melanoma has increased dramatically over the last 50 years. It accounts for most cases of skin cancer deaths. Early diagnosis leads to remission in 90% of cases of melanoma; conversely, for melanoma at more advanced stages, prognosis becomes more unfavorable also because dvanced melanoma is often resistant to pharmacological and radiological therapies due to genetic plasticity, presence of cancer stem cells that regenerate the tumor, and efficient elimination of drugs. This review illustrates the role of autophagy in tumor progression and resistance to therapy, focusing on molecular _targets for future drugs.

Keywords: acid ceramidase; autophagy; ceramides; melanoma; multidrug resistance; sphingolipids.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Ceramide and sphingosine-1-P regulate and stimulate opposite cellular pathways. The former has a pro-apoptotic effect and blocks cell replication, the latter stimulates cells to proliferate. AC balances ceramides and sphingosine levels. Since sphingosine is then converted to sphingosine-1-P by sphingosine kinase, AC has a direct role in regulating cell life.
Figure 2
Figure 2
Autophagy is induced in response to starvation, reactive oxygen species, hypoxia, infection, and drugs. Autophagy begins with the formation of the phagophore, a step mediated by the ULK1 complex. Next, phagophore nucleation requires the PI3K complex, which consists of ATG14L, VPS34, Beclin-1, and VPS15 proteins. Autophagosome formation requires the lipidation of LC3 to form LC3II. Finally, the autophagosome fuses with a lysosome forming the autophagolysosome, leading to the degradation of the sequestered organelles and cytosolic proteins.
Figure 3
Figure 3
The ceramide–sphingolipid axis contributes to regulate the fate of cells during autophagy. Balanced levels of ceramides activate autophagy through the inhibition of AKT and, consequently, of mTOR (protective autophagy). While the levels of ceramides increase, the over-activation of autophagy leads the cell to autophagic cell death through JNK-c-Jun and Beclin1 signaling.
Figure 4
Figure 4
Schematic model of the role of autophagy during cancer progression. Proficient autophagy is blocked during cell transformation and restored in the advanced phases of tumor progression.
See this image and copyright information in PMC

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