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Published on: May 18, 2018
Targeting sphingosine kinase-1 to inhibit melanoma
SubbaRao V Madhunapantula1, Jeremy Hengst, Raghavendra Gowda
1Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
Abstract:
Resistance to therapies develops rapidly for melanoma leading to more aggressive disease. Therefore, agents are needed that specifically inhibit proteins or pathways controlling the development of this disease, which can be combined, dependent on genes deregulated in a particular patient's tumors. This study shows that elevated sphingosine-1-phosphate (S-1-P) levels resulting from increased activity of sphingosine kinase-1 (SPHK1) occur in advanced melanomas. Targeting SPHK1 using siRNA decreased anchorage-dependent and -independent growth as well as sensitized melanoma cells to apoptosis-inducing agents. Pharmacological SPHK1 inhibitors SKI-I but not SKI-II decreased S-1-P content, elevated ceramide levels, caused a G2-M block and induced apoptotic cell death in melanomas. Targeting SPHK1 using siRNA or the pharmacological agent called SKI-I decreased the levels of pAKT. Furthermore, SKI-I inhibited the expression of CYCLIN D1 protein and increased the activity of caspase-3/7, which in turn led to the degradation of PARP. In animals, SKI-I but not SKI-II retarded melanoma growth by 25-40%. Thus, targeting SPHK1 using siRNAs or SKI-I has therapeutic potential for melanoma treatment either alone or in combination with other targeted agents.
Insights
Targeting sphingosine kinase-1 (SPHK1) with inhibitors shows promise for melanoma treatment. This approach reduces tumor growth and increases cancer cell death, offering new therapeutic strategies for advanced melanoma.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Melanoma exhibits rapid resistance to therapies, necessitating novel treatment strategies.
- Identifying specific molecular targets is crucial for developing combination therapies tailored to individual patient tumors.
Purpose of the Study:
- To investigate the role of sphingosine-1-phosphate (S-1-P) and sphingosine kinase-1 (SPHK1) in advanced melanoma.
- To evaluate the therapeutic potential of targeting SPHK1 in melanoma treatment.
Main Methods:
- Utilized small interfering RNA (siRNA) to inhibit SPHK1 activity.
- Employed pharmacological SPHK1 inhibitors (SKI-I and SKI-II).
- Assessed effects on cell growth, apoptosis, cell cycle progression, and molecular signaling pathways (pAKT, CYCLIN D1, caspase-3/7, PARP).
- Evaluated tumor growth in animal models.
Main Results:
- Elevated S-1-P levels and increased SPHK1 activity were observed in advanced melanomas.
- SPHK1 inhibition via siRNA or SKI-I reduced melanoma cell growth and sensitized cells to apoptosis.
- SKI-I treatment decreased S-1-P, increased ceramide, induced G2-M cell cycle arrest, and promoted apoptosis.
- SKI-I inhibited pAKT, decreased CYCLIN D1, activated caspase-3/7, and led to PARP degradation.
- SKI-I significantly retarded melanoma tumor growth in vivo.
Conclusions:
- SPHK1 is a key regulator in advanced melanoma progression.
- Targeting SPHK1 with siRNA or SKI-I demonstrates significant therapeutic potential for melanoma.
- SPHK1 inhibition offers a promising strategy for melanoma treatment, potentially in combination therapies.
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