Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Cellular Prion Protein Enhances Drug Resistance of Colorectal Cancer Cells via Regulation of a Survival Signal Pathway

  • Lee, Jun Hee (Department of Pharmacology and Toxicology, University of Alabama at Birmingham School of Medicine) ;
  • Yun, Chul Won (Medical Science Research Institute, Soonchunhyang University Seoul Hospital) ;
  • Lee, Sang Hun (Medical Science Research Institute, Soonchunhyang University Seoul Hospital)
  • Received : 2017.02.20
  • Accepted : 2017.06.14
  • Published : 2018.05.01
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Abstract

Anti-cancer drug resistance is a major problem in colorectal cancer (CRC) research. Although several studies have revealed the mechanism of cancer drug resistance, molecular targets for chemotherapeutic combinations remain elusive. To address this issue, we focused on the expression of cellular prion protein ($PrP^C$) in 5-FU-resistant CRC cells. In 5-FU-resistant CRC cells, $PrP^C$ expression is significantly increased, compared with that in normal CRC cells. In the presence of 5-FU, $PrP^C$ increased CRC cell survival and proliferation by maintaining the activation of the PI3K-Akt signaling pathway and the expression of cell cycle-associated proteins, including cyclin E, CDK2, cyclin D1, and CDK4. In addition, $PrP^C$ inhibited the activation of the stress-associated proteins p38, JNK, and p53. Moreover, after treatment of 5-FU-resistant CRC cells with 5-FU, silencing of $PrP^C$ triggered apoptosis via the activation of caspase-3. These results indicate that $PrP^C$ plays a key role in CRC drug resistance. The novel strategy of combining chemotherapy with $PrP^C$ targeting may yield efficacious treatments of colorectal cancer.

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References

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