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A Pipeline to Investigate the Structures and Signaling Pathways of Sphingosine 1-Phosphate Receptors
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A Pipeline to Investigate the Structures and Signaling Pathways of Sphingosine 1-Phosphate Receptors

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Sphingosine-1-Phosphate Receptor-1 Promotes Environment-Mediated and Acquired Chemoresistance

Veronica Lifshitz1, Saul J Priceman2, Wenzhao Li1

  • 1Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.

Molecular Cancer Therapeutics
|July 19, 2017
PubMed

Insights

Human bone marrow cells promote neuroblastoma chemoresistance by increasing sphingosine-1-phosphate receptor-1 (S1PR1). Targeting S1PR1 with FTY720 drug sensitizes resistant neuroblastoma to chemotherapy.

Area of Science:

  • Oncology
  • Cancer Biology
  • Pharmacology

Background:

  • Drug resistance is a significant obstacle in developing effective and lasting cancer therapies.
  • Understanding acquired and environment-mediated drug resistance (EMDR) mechanisms is crucial for overcoming treatment failure.
  • Neuroblastoma (NB) recurrence is often linked to chemotherapy resistance.

Purpose of the Study:

  • To investigate the role of sphingosine-1-phosphate receptor-1 (S1PR1) in mediating chemoresistance in neuroblastoma.
  • To explore S1PR1 as a potential therapeutic target for overcoming drug resistance in NB.

Main Methods:

  • Utilized neuroblastoma (NB) as a model to study chemoresistance.
  • Investigated the effect of human bone marrow-mesenchymal stromal cells on NB drug resistance.
  • Assessed the impact of S1PR1 modulation (shRNA, overexpression) on NB cell apoptosis and chemoresistance.
  • Examined the role of JAK-STAT3 signaling in S1PR1-mediated resistance.
  • Evaluated the efficacy of FTY720, an S1PR1 antagonist, in preclinical models (in vitro and xenografts).

Main Results:

  • Human bone marrow-mesenchymal stromal cells induce tumor S1PR1 expression, conferring chemotherapy resistance to NB cells.
  • Targeting S1PR1 with shRNA enhances etoposide-induced apoptosis and abrogates EMDR in NB.
  • S1PR1 overexpression protects NB cells from multidrug-induced apoptosis via JAK-STAT3 activation.
  • Elevated S1PR1 and STAT3 activation correlate with acquired etoposide resistance in human NB cells.
  • FTY720 treatment sensitizes drug-resistant NB cells to etoposide in vitro and in vivo.

Conclusions:

  • S1PR1 is identified as a critical mediator of both environment-mediated drug resistance (EMDR) and acquired chemoresistance in neuroblastoma.
  • Targeting S1PR1 represents a promising strategy to enhance the efficacy of chemotherapy in drug-resistant neuroblastoma.
  • FTY720 demonstrates potential as a therapeutic agent to overcome chemoresistance in NB.

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