Oncotarget

Research Papers:

Acquired resistance to 5-fluorouracil via HSP90/Src-mediated increase in thymidylate synthase expression in colon cancer

Ji-Young Ahn _, Ji-Sun Lee, Hye-Young Min and Ho-Young Lee

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Oncotarget. 2015; 6:32622-32633. https://doi.org/10.18632/oncotarget.5327

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Abstract

Ji-Young Ahn1,*, Ji-Sun Lee1,*, Hye-Young Min1, Ho-Young Lee1

1College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea

*These authors have contributed equally to this work

Correspondence to:

Ho-Young Lee, e-mail: hylee135@snu.ac.kr

Keywords: 5-fluorouracil, colon cancer, HSP90, Src

Received: May 05, 2015     Accepted: September 11, 2015     Published: September 23, 2015

ABSTRACT

5-fluorouracil (5-FU), one of the first-line chemotherapeutic agents for the treatment of gastrointestinal malignancies, has shown limited efficacy. The expression of thymidylate synthase (TYMS) has been reported to be associated with the resistance to 5-FU. Here, we demonstrate that the enhanced HSP90 function and subsequent activation of Src induce expression of TYMS and acquired resistance to 5-FU in colon cancer. We show that the persistent 5-FU treatment granted 5-FU-sensitive HCT116 colon cancer cells morphologic, molecular, and behavioral characteristic of the epithelial-mesenchymal transition (EMT), contributing to emergence of acquired resistance to 5-FU. HCT116/R, a HCT116 colon cancer cell subline carrying acquired resistance to 5-FU, showed increased expression and activation of HSP90’s client proteins and transcriptional up-regulation of TYMS. Forced overexpression of HSP90 or constitutive active Src in HCT116 cells increased TYMS expression. Conversely, pharmacological blockade of HSP90 or Src in HCT116/R cells effectively suppressed the changes involved in 5-FU resistance in vitro and xenograft tumor growth, hematogenous spread, and metastatic tumor development in vivo. This study suggests a novel function of HSP90-Src pathway in regulation of TYMS expression and acquisition of 5-FU resistance. Thus, therapeutics targeting this pathway may be an effective clinical strategy to overcome 5-FU resistance in colon cancer.


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