2020 Fiscal Year Final Research Report
A research of Camptothecin resistance determined by regulation of topoisomerase I degradation mediated by PTEN in colon cancer
Project/Area Number |
19K23917
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Research Category |
Grant-in-Aid for Research Activity Start-up
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Allocation Type | Multi-year Fund |
Review Section |
0901:Oncology and related fields
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Research Institution | Kyushu University |
Principal Investigator |
ZAITSU Yoko 九州大学, 医学研究院, 共同研究員 (50843497)
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Project Period (FY) |
2019-08-30 – 2021-03-31
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Keywords | Colon cancer / Chemoresistance / PTEN / Topoisomerase Ⅰ |
Outline of Final Research Achievements |
Using C2 cells, our group confirmed that PTEN regulates topoisomerase I (topoI) degradation through DNA-dependent protein kinase (DNA-PKcs) activity. Low expression of PTEN leads to higher DNA-PKcs activity causing higher phosphorylates topoI on serine 10 (topoI-pS10) level. This leads to rapid topoI degradation and cause CPT resistance. This phenomenon was also seen in human colon cancer cell lines such as HCT15. Among the patients that show high topoI-pS10 protein expression by IHC in colon cancer specimen, the tumor show progression in a relatively low dosage of CPT comparing to patients with low topoI-pS10 protein expression. We assume that this finding can lead to a new biomarker to estimate the resistance of CPT and also can be applied to developping a new agent that will reduce CPT resistance.
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Free Research Field |
医学
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Academic Significance and Societal Importance of the Research Achievements |
トポイソメラーゼ阻害薬に分類されるイリノテカンは切除不能な進行再発大腸癌の長期コントロールや局所進行直腸癌の縮小を狙った術前治療など大腸・直腸癌においては重要な役割を果たす。本研究によりトポイソメラーゼ阻害薬の耐性メカニズムの一因によく知られている、がん抑制遺伝子PTENが関与していることが分かった。また臨床検体を用いた免疫染色において、トポイソメラーゼの分解産物の発現とイリノテカンの耐性に関与がある可能性が示唆された。将来的に抗癌剤の治療効果を推測するバイオマーカーの開発や耐性を回避する新規の薬剤の開発のきっかけになる点で学術的、社会的意義があると考える。
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