Role of SPTSSB-Regulated de Novo Sphingolipid Synthesis in Prostate Cancer Depends on Androgen Receptor Signaling
Pedro Costa-Pinheiro,
Abigail Heher,
Michael H. Raymond,
Kasey Jividen,
Jeremy JP. Shaw,
Bryce M. Paschal,
Susan J. Walker,
Todd E. Fox,
Mark Kester
Affiliations
Pedro Costa-Pinheiro
Department of Pathology, University of Virginia, Charlottesville, VA 22903, USA
Abigail Heher
Department of Biology, University of Virginia, Charlottesville, VA 22903, USA
Michael H. Raymond
Neuroscience Graduate Program, University of Virginia, Charlottesville, VA 22903, USA
Kasey Jividen
Center for Cell Signaling, University of Virginia, Charlottesville, VA 22903, USA
Jeremy JP. Shaw
Department of Pathology, University of Virginia, Charlottesville, VA 22903, USA
Bryce M. Paschal
Center for Cell Signaling, University of Virginia, Charlottesville, VA 22903, USA; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22903, USA
Susan J. Walker
Department of Pharmacology, University of Virginia, Charlottesville, VA 22903, USA
Todd E. Fox
Department of Pharmacology, University of Virginia, Charlottesville, VA 22903, USA
Mark Kester
Department of Pharmacology, University of Virginia, Charlottesville, VA 22903, USA; nanoSTAR Institute, University of Virginia, Charlottesville, VA 22903, USA; Corresponding author
Summary: Anti-androgens are a common therapy in prostate cancer (PCa) targeting androgen receptor (AR) signaling. However, these therapies fail due to selection of highly aggressive AR-negative cancer cells that have no therapeutic options available. We demonstrate that elevating endogenous ceramide levels with administration of exogenous ceramide nanoliposomes (CNLs) was efficacious in AR-negative cell lines with limited efficacy in AR-positive cells. This effect is mediated through reduced de novo sphingolipid synthesis in AR-positive cells. We show that anti-androgens elevate de novo generation of sphingolipids via SPTSSB, a rate-limiting mediator of sphingolipid generation. Moreover, pharmacological inhibition of AR increases the efficacy of CNL in AR-positive cells through de novo synthesis, while SPTSSB knockdown limited CNL's efficacy in AR-negative cells. Alluding to clinical relevance, SPTSSB is upregulated in patients with advanced PCa after anti-androgens treatment. These findings emphasize the relevance of AR regulation upon sphingolipid metabolism and the potential of CNL as a PCa therapeutic.
