Development of new therapeutic strategies to overcome cancer radioresistance; focusing on molecules that are increased in resistant cell lines

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K17258
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52040:Radiological sciences-related
• Research Institution: Niigata University
• Principal Investigator: KANEMITSU Yoshitomi 新潟大学, 医歯学総合病院, 特任助教 (30752943)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 放射線耐性細胞 / プロテオミクス / peroxiredoxin / PDI

Outline of Final Research Achievements

Radiotherapy is an essential component of cancer therapy. However, radioresistance remains a major obstacle to effective radiotherapy. The purpose of this study was to reveal new molecular mechanisms underlying radioresistance. To identify and quantification of novel radioresistance-related proteins, we conducted quantitative proteomic profiling on SAS and radioresistant cell lines (SAS-R). We found that protein disulfide isomerase (PDI) family proteins and peroxiredoxin 4 (Prx4) were significantly increased in SAS-R cells, as compared to SAS. Further, we also showed that knockdown of Prx4 in SAS-R cells leads to decreased radioresistance and resistance to H2O2.
These results indicated that Prx4-PDI is one of the key molecules contributing to radioresistance in SAS-R cells. There is a possibility that specific suppression of Prx4 can be a novel approach to overcoming cancer radioresistance.

Free Research Field

医療薬学、分析化学

Academic Significance and Societal Importance of the Research Achievements

放射線治療は、がん治療における重要な治療選択肢の一つである。しかし、放射線耐性を獲得するがん細胞が存在し、これによる再発が問題となる。したがって、放射線耐性化機序の解明と新規治療戦略の開発が切望されている。本研究では、口腔扁平上皮癌細胞株 SAS およびその放射線耐性細胞株である SAS-R を用いた解析から、タンパク質のフォールディングに関わる PDI ファミリータンパク質が耐性細胞株で増加していること及び過酸化水素除去能を持つことが知られている Prx4 が、耐性能に関与していることを明らかにした。これらの成果は、放射線耐性化機序の理論構築と新規治療戦略開発への応用が期待される。