Inhibition of Heat-shock Protein 27 Reduces 5-Fluorouracil-acquired Resistance in Human Colon Cancer Cells

Abstract

Background/Aim: In previous work we showed that expression of heat-shock protein 27 (HSP27; encoded by HSPB1) was associated with inherent resistance to . However, the relationship between HSP27 and acquired resistance remains unknown. Materials and Methods: We generated an acquired resistance model (WiDr-R) of a colon cancer cell line by exposing WiDr cells to 5-FU. Cell viability assays under treatment with 5-FU, as well as down-regulation of HSP27 using small interfering HSP27 RNA, were performed. HSP27 mRNA and protein expression was analyzed using real-time polymerase chain reaction and western blotting. Results: 5-FU-acquired resistance induced overexpression of HSP27 mRNA and protein levels in WiDr-R cells. Furthermore, siRNA knockdown of HSP27 in WiDr-R cells reduced 5-FUacquired resistance. Conclusion: These findings demonstrate that HSP27 is associated with 5-FU resistance in human colon cancer cell cells and suggest that HSP27 regulation represents a novel approach to overcoming chemoresistance in colorectal cancer.Colorectal cancer (CRC) is a very common disease worldwide. In advanced cancer, systemic chemotherapy and surgery are key treatment approaches. Currently, systemic chemotherapy for CRC has progressed remarkably. 5-Fluorouracil (5-FU) is a classic and very important cytotoxic anticancer drug; this treatment is commonly combined with other cytotoxic drugs such as oxaliplatin, and irinotecan. Furthermore, a paradigm shift has occurred in the use of molecular target drugs. Administration of vascular endothelial growth factor inhibitors (bevacizumab/ramucirumab) and epidermal growth factor receptor (EGFR) inhibitors (cetuximab/panitumumab) has improved the prognosis of advanced unresectable or recurrent CRC by up to approximately 30 months (1-3).However, resistance to 5-FU-based chemotherapy, which is widely used to treat CRC, remains an insurmountable clinical challenge. Therefore, novel approaches to overcoming 5-FU resistance are required, for which several strategies and drugs have been identified (4-6). Heat-shock proteins, including heat-shock protein 27 (HSP27; encoded by HSPB1), act as molecular chaperones in protein-protein interactions under physiological conditions. Additionally, HSP27 expression is increased in various types of malignant diseases (7-9). Furthermore, a relationship between HSP27 overexpression and drug resistance has been reported (9-11). We have previously suggested that HSP27 is associated with 5-FU resistance in certain human colon cancer cell lines. Cell lines with higher levels of HSP27 expression showed a higher degree of 5-FU resistance compared to those with lower expression levels (12). Additionally, in experiments using cell lines with high HSP27 expression (inherently resistant to 5-FU according to our hypothesis), downregulation of HSP27 using small interfering RNA (siRNA) or short hairpin RNA reduced 5-FU resistance (12, 13). Furthermore, in the same setting, down-regulation of HSP27 using apatorsen, an antisense oligonucleotide that targets HSP27, reduced...

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