Downregulation of Critical Oncogenes by the Selective SK2 Inhibitor ABC294640 Hinders Prostate Cancer Progression.

Abstract

UNLABELLED:

The bioactive sphingolipid sphingosine-1-phosphate (S1P) drives several hallmark processes of cancer, making the enzymes that synthesize S1P, that is, sphingosine kinase 1 and 2 (SK1 and SK2), important molecular targets for cancer drug development. ABC294640 is a first-in-class SK2 small-molecule inhibitor that effectively inhibits cancer cell growth in vitro and in vivo. Given that AR and Myc are two of the most widely implicated oncogenes in prostate cancer, and that sphingolipids affect signaling by both proteins, the therapeutic potential for using ABC294640 in the treatment of prostate cancer was evaluated. This study demonstrates that ABC294640 abrogates signaling pathways requisite for prostate cancer growth and proliferation. Key findings validate that ABC294640 treatment of early-stage and advanced prostate cancer models downregulate Myc and AR expression and activity. This corresponds with significant inhibition of growth, proliferation, and cell-cycle progression. Finally, oral administration of ABC294640 was found to dramatically impede xenograft tumor growth. Together, these pre-clinical findings support the hypotheses that SK2 activity is required for prostate cancer function and that ABC294640 represents a new pharmacological agent for treatment of early stage and aggressive prostate cancer.

IMPLICATIONS:

Sphingosine kinase inhibition disrupts multiple oncogenic signaling pathways that are deregulated in prostate cancer.

• Authors: Randy S Schrecengost, Staci N Keller, Matthew J Schiewer, Karen E Knudsen, Charles D Smith
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 13 Issue 12 Pg. 1591-601 (Dec 2015) ISSN: 1557-3125 [Electronic] United States
• PMID: 26271487 (Publication Type: Journal Article)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• AR protein, human
• Antineoplastic Agents
• KCNN2 protein, human
• MYC protein, human
• Proto-Oncogene Proteins c-myc
• Pyridines
• Receptors, Androgen
• Small-Conductance Calcium-Activated Potassium Channels
• 3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide
• Adamantane

Topics

• Adamantane (administration & dosage, analogs & derivatives, pharmacology)
• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Cell Line, Tumor
• Disease Progression
• Down-Regulation
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Male
• Mice
• Prostatic Neoplasms (drug therapy, genetics, metabolism)
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• Pyridines (administration & dosage, pharmacology)
• Receptors, Androgen (genetics, metabolism)
• Signal Transduction (drug effects)
• Small-Conductance Calcium-Activated Potassium Channels (antagonists & inhibitors)
• Xenograft Model Antitumor Assays