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Peer-reviewedCC BY-NC 4.0Biomolecules & Therapeutics

Acquired TRAIL Resistance Promotes Cancer Stemness and Malignant Behavior through CD44-SPHK1-STAT3 Signaling in Colorectal Cancer

  • Se Lim Kim1,2
  • Byung Chul Jin1,2
  • Seung Young Seo1,2
  • Sang Wook Kim1,2
  1. 1Department of Internal Medicine, Research Institute of Clinical Medicine of Jeonbuk National University, Jeonju 54907 Jeonju 54907 Republic of Korea
  2. 2Biomedical Research Institute of Jeonbuk National University Hospital Jeonju 54907 Republic of Korea
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Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent; however, the frequent emergence of acquired TRAIL resistance limits its therapeutic efficacy in colorectal cancer (CRC). Cancer stem cells (CSCs) contribute to therapeutic resistance, recurrence, and metastatic progression, yet the relationship between TRAIL resistance and CSC enrichment remains unclear. Here, we demonstrate that acquired TRAIL resistance drives CD44-dependent stemness and malignant behavior in CRC. TRAIL-resistant HCT116 cells (HCT116-TR) exhibited increased sphere formation, enhanced motility, and a marked expansion of CD44⁺ cells. CD44⁺ HCT116-TR cells isolated by antibody-based sorting displayed the strongest CSC-like properties, heightened TRAIL resistance, and robust activation of the SPHK1/STAT3 axis, indicating that CD44 upregulation is a major determinant of TRAIL-induced aggressiveness. In vivo, CD44⁺ HCT116-TR cells induced extensive lung metastasis with elevated CD44, p-SPHK1, and p-STAT3 expression, whereas CD44-deficient mice injected with TRAIL-resistant CMT-93 cells showed minimal metastatic burden and reduced pathway activation, confirming the essential role of CD44 in TRAIL-associated metastasis. TCGA colon cancer analysis further revealed CD44 overexpression in tumors and its association with poor overall survival. Collectively, these findings show that acquired TRAIL resistance promotes CD44-mediated CSC expansion and metastatic potential through SPHK1/STAT3 activation, highlighting CD44 as a key therapeutic target in CRC.

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Cite

BibTeXRIS
BibTeX
@article{kim2026acquired,
  title = {{Acquired TRAIL Resistance Promotes Cancer Stemness and Malignant Behavior through CD44-SPHK1-STAT3 Signaling in Colorectal Cancer}},
  author = {Se Lim Kim and Byung Chul Jin and Seung Young Seo and Sang Wook Kim},
  journal = {Biomolecules \& Therapeutics},
  year = {2026},
  month = nov,
  doi = {10.4062/biomolther.2026.083},
  url = {https://doi.org/10.4062/biomolther.2026.083},
  note = {CC BY-NC 4.0},
}
RIS
TY  - JOUR
TI  - Acquired TRAIL Resistance Promotes Cancer Stemness and Malignant Behavior through CD44-SPHK1-STAT3 Signaling in Colorectal Cancer
AU  - Se Lim Kim
AU  - Byung Chul Jin
AU  - Seung Young Seo
AU  - Sang Wook Kim
PY  - 2026
DA  - 2026/11/01
JO  - Biomolecules & Therapeutics
DO  - 10.4062/biomolther.2026.083
UR  - https://doi.org/10.4062/biomolther.2026.083
AB  - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent; however, the frequent emergence of acquired TRAIL resistance limits its therapeutic efficacy in colorectal cancer (CRC). Cancer stem cells (CSCs) contribute to therapeutic resistance, recurrence, and metastatic progression, yet the relationship between TRAIL resistance and CSC enrichment remains unclear. Here, we demonstrate that acquired TRAIL resistance drives CD44-dependent stemness and malignant behavior in CRC. TRAIL-resistant HCT116 cells (HCT116-TR) exhibited increased sphere formation, enhanced motility, and a marked expansion of CD44⁺ cells. CD44⁺ HCT116-TR cells isolated by antibody-based sorting displayed the strongest CSC-like properties, heightened TRAIL resistance, and robust activation of the SPHK1/STAT3 axis, indicating that CD44 upregulation is a major determinant of TRAIL-induced aggressiveness. In vivo, CD44⁺ HCT116-TR cells induced extensive lung metastasis with elevated CD44, p-SPHK1, and p-STAT3 expression, whereas CD44-deficient mice injected with TRAIL-resistant CMT-93 cells showed minimal metastatic burden and reduced pathway activation, confirming the essential role of CD44 in TRAIL-associated metastasis. TCGA colon cancer analysis further revealed CD44 overexpression in tumors and its association with poor overall survival. Collectively, these findings show that acquired TRAIL resistance promotes CD44-mediated CSC expansion and metastatic potential through SPHK1/STAT3 activation, highlighting CD44 as a key therapeutic target in CRC.
SN  - 1976-9148
SN  - 2005-4483
ER  -