Abstract
Clear cell renal cell carcinoma (ccRCC) is characterized by intratumoral hypoxia and chemoresistance. The hypoxia-inducible factors HIF1α and HIF2α play a crucial role in ccRCC initiation and progression. We previously identified the sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) pathway as a new modulator of HIF1α and HIF2α under hypoxia in various cancer cell models. Here, we report that FTY720, an inhibitor of the S1P signaling pathway, inhibits both HIF1α and HIF2α accumulation in several human cancer cell lines. In a ccRCC heterotopic xenograft model, we show that FTY720 transiently decreases HIF1α and HIF2α intratumoral level and modifies tumor vessel architecture within 5 days of treatment, suggesting a vascular normalization. In mice bearing subcutaneous ccRCC tumor, FTY720 and a gemcitabine-based chemotherapy alone display a limited effect, whereas, in combination, there is a significant effect on tumor size without toxicity. Noteworthy, administration of FTY720 for 5 days before chemotherapy is not associated with a more effective tumor control, suggesting a mode of action mainly independent of the vascular remodeling. In conclusion, these findings demonstrate that FTY720 could successfully sensitize ccRCC to chemotherapy and establish this molecule as a potent therapeutic agent for ccRCC treatment, independently of drug scheduling. Mol Cancer Ther; 15(10); 2465-74. ©2016 AACR.
Highlights
Clear cell renal cell carcinoma accounts for around 3% of adult cancers
We previously reported that the sphingosine kinase 1 (SphK1)/sphingosine 1-phosphate (S1P)/S1P1 pathway is a regulator of both HIF1a and HIF2a during hypoxia in multiple cancer cell lineages, including prostate cancer and Clear cell renal cell carcinoma (ccRCC) [17,18,19]
To evaluate the relevance of inhibiting this pathway with regard to HIF1a and HIF2a expression in cancer cells, we relied on FTY720, a drug that antagonizes the S1P1 receptor [23] and inhibits SphK1 [24,25,26, 32]
Summary
Clear cell renal cell carcinoma (ccRCC) accounts for around 3% of adult cancers. Its prognosis is closely related with disease stage, with 5-year survival rates ranging from 90% to 10% for stage I and stage IV disease, respectively. The last decade has witnessed major advances in the understanding of ccRCC biology, and a number of effective treatments are available, such as antiangiogenic agents and mTOR inhibitors [1, 2]. Because numerous studies have exhibited the major role of hypoxia-inducible factors HIF1a and HIF2a, master regulators of cell response to hypoxia, in ccRCC initiation and progression [3,4,5], their inhibition may represent a potent therapeutic strategy. HIF transcription factors control the expression of numerous target genes contributing to tumor angiogenesis, invasion, metastasis, and therapeutic failure [6]. HIF1a and HIF2a stimulate the production of angiogenic factors, such as VEGF, an independent prognostic marker in ccRCC [7], Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/)
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