論文 - 詳細
| RRC ID | 63171 |
|---|---|
| 著者 | Pan YR, Wu CE, Yeh CN. |
| タイトル | ATM Inhibitor Suppresses Gemcitabine-Resistant BTC Growth in a Polymerase θ Deficiency-Dependent Manner. |
| ジャーナル | Biomolecules |
| Abstract |
Patients with advanced biliary tract cancer (BTC) inevitably experience progression after first-line, gemcitabine-based chemotherapy, due to chemo-resistance. The genetic alterations of DNA damage repair (DDR) genes are usually determined in BTC tumors. In this study, we found that the POLQ mRNA levels are downregulated and the ataxia-telangiectasia mutated (ATM) inhibitor AZD0156 was more sensitive in gemcitabine-resistant BTC sublines than in the parental cell lines. The knockdown of DNA polymerase θ does not affect cell proliferation, but its combination with the ATM inhibitor facilitated cell death in gemcitabine-resistant and gemcitabine-intensive BTC cells. Moreover, in the DNA damage caused by photon, hydrogen peroxide, or chemotherapy drugs, synthetic lethal interactions were found in combination with ATM inhibition by AZD0156 and DNA polymerase θ depletion, resulting in increased DNA damage accumulation and micronucleus formation, as well as reduced cell survival and colony formation. Collectively, our results reveal that ATM acts as a potential target in gemcitabine-resistant and DNA polymerase θ-deficient BTC. |
| 巻・号 | 10(11) |
| 公開日 | 2020-11-9 |
| DOI | 10.3390/biom10111529 |
| PII | biom10111529 |
| PMID | 33182492 |
| PMC | PMC7697425 |
| MeSH | Ataxia Telangiectasia Mutated Proteins / antagonists & inhibitors* Biliary Tract Neoplasms / pathology* Cell Line, Tumor DNA-Directed DNA Polymerase / deficiency* DNA-Directed DNA Polymerase / genetics Deoxycytidine / analogs & derivatives* Deoxycytidine / pharmacology Drug Resistance, Neoplasm / drug effects* Gemcitabine Gene Knockdown Techniques Humans Protein Kinase Inhibitors / pharmacology* |
| IF | 4.082 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | RBE(RCB1292) HuCCT1(RCB1960) SSP-25(RCB1293) TGBC24TKB(RCB1196) TFK-1(RCB2537) |