Targeting S1PR1/STAT3 loop abrogates desmoplasia and chemosensitizes pancreatic cancer to gemcitabine

Abstract

Rationale: Pancreatic cancer is associated with poor prognosis with a 5-year survival rate of less than 6%. Approximately 90% of pancreatic cancer patients harbor somatic mutations in the KRAS gene. Multiple lines of evidence suggest a persistent activation of STAT3 in KRAS-driven oncogenesis contributing to desmoplasia and gemcitabine resistance. Sphingosine 1-phosphate receptor 1 (S1PR1) is an integral component of tumor progression and maintains an activated state of STAT3. FTY720 is an approved drug for multiple sclerosis and acts as a functional antagonist for S1PR1. Here we explored the potential utility of FTY720 to target S1PR1/STAT3 and other major signaling pathways in pancreatic cancer, and sought proof-of-principle for repurposing FTY720 for the treatment of pancreatic cancer.Methods: We examined the activity of FTY720 in the proliferation, apoptosis, and cell cycle assays in human and mouse pancreatic cancer model systems. Further, we studied the efficacy of using a combination of FTY720 and gemcitabine as opposed to individual agents in vitro as well as in vivoResults: Treatment of human and mouse pancreatic cancer cells with FTY720 resulted in inhibition of growth, increased apoptosis, and cell cycle arrest. FTY720 in combination with gemcitabine breached the mitochondrial membrane potential, altered the S1PR1-STAT3 loop, and inhibited epithelial to mesenchymal (EMT) transition. Data from murine models exhibited a marked reduction in the tumor size, increased apoptosis, inhibited NF-κB, S1PR1/STAT3, Shh signaling and desmoplasia, modulated the expression of gemcitabine-metabolizing transport enzymes, and restored the expression of tumor suppressor gene PP2A.Conclusion: Taken together, our results established FTY720 as a propitious molecule, which increases the efficacy of gemcitabine and represents a promising agent in the management of pancreatic cancer.

Galectin-1 Promotes Metastasis in Gastric Cancer Through a Sphingosine-1-Phosphate Receptor 1-Dependent Mechanism

“…It has also been reported that STAT3 regulated expression of S1PR1. Not only can STAT3 mediate S1PR1 expression, but S1PR1 activates STAT3 through the Jak2 tyrosine kinase [24,37,38]. We speculate that Gal-1 activates S1PR1 via activation of an "H-Ras -MEK/ERK -STAT3/S1PR1" axis in GC.…”

DYRK1A inhibition suppresses STAT3/EGFR/Met signalling and sensitizes EGFR wild‐type NSCLC cells to AZD9291

“…The transcription factor STAT3 is overexpressed in multiple cancer types and modulates the expression of genes involved in cell proliferation, survival and differentiation . Furthermore, STAT3 activation confers cancer cell resistance to anti‐cancer drugs such as trastuzumab and cisplatin, and targeting STAT3 is a potential strategy for sensitizing cancer cells to chemotherapy agents . STAT3 signalling is also implicated in mediating resistance to EGFR‐TKI therapy, and targeting STAT3 in conjunction with the EGFR results in enhanced antitumour activity .…”

“…23 Furthermore, STAT3 activation confers cancer cell resistance to anti-cancer drugs such as trastuzumab and cisplatin, and targeting STAT3 is a potential strategy for sensitizing cancer cells to chemotherapy agents. [24][25][26][27] STAT3 signalling is also implicated in mediating resistance to EGFR-TKI therapy, and targeting STAT3 in conjunction with the EGFR results in enhanced antitumour activity. 28 Thus, we hypothesized that targeting the upstream activators of STAT3 might be an attractive strategy to overcome EGFR-TKI resistance.…”

Regulatory role of SphK1 in TLR7/9‐dependent type I interferon response and autoimmunity

“…The membranes were blocked with 5% skim milk and antibodies were added and incubated overnight at 4°C. HRP conjugated secondary antibodies were added and immunopositive bands visualized by chemiluminescence . The source of antibodies as follows.…”