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Purpose <p>Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various tumor cell types. Although TRAIL can directly trigger cell death, cancer cells may acquire resistance to its apoptotic effects during treatment. Sphingosine kinase 1 (SPHK1) is a key regulator of cancer progression and resistance to therapy. In this study, we determined whether combining TRAIL with PF-543, a specific SPHK1 inhibitor, could circumvent TRAIL resistance in previously established TRAIL-resistant colorectal cancer cells (HCT116-TR cells).</p> Methods <p>HCT116-TR cells were treated with TRAIL and/or PF-543. Apoptotic cell death and signaling pathways were evaluated using MTT assay, colony formation assay, and flow cytometry analysis. Cell aggressiveness and cancer stemness were assessed through wound healing assay, Matrigel-coated Transwell assay, and tumorsphere formation assay. The underlying molecular mechanisms were examined by Western blotting.</p> Results <p>Combined treatment with PF-543 significantly enhanced TRAIL-induced apoptosis in HCT116-TR cells and exhibited a synergistic effect. Mechanistically, PF-543 sensitized HCT116-TR cells to TRAIL by activating the mitochondrial apoptosis pathway. Moreover, PF-543 increased TRAIL sensitivity by regulating DcR1 and DR5 through the SPHK1/S1PR1/STAT3 pathway. In addition, combination treatment reduced the aggressiveness and cancer stemness of HCT116-TR cells by modulating the epithelial-mesenchymal transition (EMT) pathway as well as cancer stemness markers.</p> Conclusion <p>We identified the molecular mechanisms underlying acquired TRAIL resistance in CRC cells and suggest that targeting SPHK1 represents a potential strategy to overcome TRAIL resistance and inhibit CRC metastasis.</p>

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The Combination of PF-543 and TRAIL Effectively Induces Apoptotic Cell Death and Inhibits Stem Cell-Like Properties Through the SPHK1/S1PR1/STAT3 Pathway in TRAIL-Resistant Colorectal Cancer Cells

  • 期刊论文

  • 发表日期：

    2025年6月5日

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  • Se Lim Kim,
  • Min Woo Shin,
  • Byung Chul Jin,
  • Seung Young Seo,
  • Sang Wook Kim

摘要

Purpose

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various tumor cell types. Although TRAIL can directly trigger cell death, cancer cells may acquire resistance to its apoptotic effects during treatment. Sphingosine kinase 1 (SPHK1) is a key regulator of cancer progression and resistance to therapy. In this study, we determined whether combining TRAIL with PF-543, a specific SPHK1 inhibitor, could circumvent TRAIL resistance in previously established TRAIL-resistant colorectal cancer cells (HCT116-TR cells).

Methods

HCT116-TR cells were treated with TRAIL and/or PF-543. Apoptotic cell death and signaling pathways were evaluated using MTT assay, colony formation assay, and flow cytometry analysis. Cell aggressiveness and cancer stemness were assessed through wound healing assay, Matrigel-coated Transwell assay, and tumorsphere formation assay. The underlying molecular mechanisms were examined by Western blotting.

Results

Combined treatment with PF-543 significantly enhanced TRAIL-induced apoptosis in HCT116-TR cells and exhibited a synergistic effect. Mechanistically, PF-543 sensitized HCT116-TR cells to TRAIL by activating the mitochondrial apoptosis pathway. Moreover, PF-543 increased TRAIL sensitivity by regulating DcR1 and DR5 through the SPHK1/S1PR1/STAT3 pathway. In addition, combination treatment reduced the aggressiveness and cancer stemness of HCT116-TR cells by modulating the epithelial-mesenchymal transition (EMT) pathway as well as cancer stemness markers.

Conclusion

We identified the molecular mechanisms underlying acquired TRAIL resistance in CRC cells and suggest that targeting SPHK1 represents a potential strategy to overcome TRAIL resistance and inhibit CRC metastasis.