Related Experiment Video

Updated: Sep 19, 2025

A Three-dimensional Model of Spheroids to Study Colon Cancer Stem Cells
06:38

A Three-dimensional Model of Spheroids to Study Colon Cancer Stem Cells

Published on: January 22, 2021

6.3K

The Combination of PF-543 and TRAIL Effectively Induces Apoptotic Cell Death and Inhibits Stem Cell-Like Properties

Se Lim Kim1,2, Min Woo Shin1,2, Byung Chul Jin1,2

  • 1Department of Internal Medicine, Research Institute of Clinical Medicine of Jeonbuk National University Medical School, 20, Geonji-ro, Deokjin-gu, Jeonju, Jeonbuk, 54907, Republic of Korea.

Digestive Diseases and Sciences
|June 4, 2025
PubMed
Abstract

Insights

Combining a TRAIL-resistant colorectal cancer (CRC) cell line with a sphingosine kinase 1 (SPHK1) inhibitor, PF-543, overcomes resistance. This combination therapy enhances apoptosis and reduces cancer stemness in CRC cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in cancer cells, but resistance can develop.
  • Sphingosine kinase 1 (SPHK1) is implicated in cancer progression and therapeutic resistance.
  • Colorectal cancer (CRC) cells can acquire resistance to TRAIL-induced apoptosis.

Purpose of the Study:

  • To investigate if combining TRAIL with a specific SPHK1 inhibitor (PF-543) can overcome TRAIL resistance in CRC cells.
  • To elucidate the molecular mechanisms by which PF-543 sensitizes TRAIL-resistant CRC cells.
  • To assess the impact of combination therapy on cancer cell aggressiveness and stemness.

Main Methods:

  • TRAIL-resistant colorectal cancer cells (HCT116-TR) were treated with TRAIL and/or PF-543.
  • Apoptosis, cell signaling, aggressiveness, and cancer stemness were evaluated using assays like MTT, Western blotting, and wound healing.
  • Molecular mechanisms were examined via Western blotting to analyze key pathways.

Main Results:

  • Combined PF-543 and TRAIL treatment synergistically enhanced apoptosis in HCT116-TR cells.
  • PF-543 sensitized cells to TRAIL by activating the mitochondrial apoptosis pathway and regulating DcR1/DR5 via the SPHK1/S1PR1/STAT3 pathway.
  • Combination therapy reduced cell aggressiveness and cancer stemness by modulating epithelial-mesenchymal transition (EMT) and stemness markers.

Conclusions:

  • Targeting SPHK1 with PF-543 is a viable strategy to overcome TRAIL resistance in colorectal cancer.
  • The SPHK1/S1PR1/STAT3 pathway plays a critical role in mediating TRAIL resistance in CRC.
  • Combination therapy holds potential for inhibiting CRC metastasis and improving treatment outcomes.
Keywords:
ApoptosisCancer stem cellsChemoresistanceColorectal cancerInvasionPF-543S1PR1SPHK1STAT3TRAIL

More Related Videos

Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies09:29

Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies

Published on: September 30, 2016

13.9K
Exploring the Two Herb Combination Strategy to Treat Injured PC12 Cells10:33

Exploring the Two Herb Combination Strategy to Treat Injured PC12 Cells

Published on: November 18, 2022

1.4K

Related Concept Videos

Combination Therapies and Personalized Medicine02:50

Combination Therapies and Personalized Medicine

Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
5.1K
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
7.8K
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
6.6K
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
6.9K