論文

査読有り 国際誌
2021年8月31日

PDK2 leads to cisplatin resistance through suppression of mitochondrial function in ovarian clear cell carcinoma.

Cancer science
  • Sachiko Kitamura
  • ,
  • Ken Yamaguchi
  • ,
  • Ryusuke Murakami
  • ,
  • Yoko Furutake
  • ,
  • Koichiro Higasa
  • ,
  • Kaoru Abiko
  • ,
  • Junzo Hamanishi
  • ,
  • Tsukasa Baba
  • ,
  • Noriomi Matsumura
  • ,
  • Masaki Mandai

112
11
開始ページ
4627
終了ページ
4640
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1111/cas.15125

Ovarian clear cell carcinoma (CCC) exhibits an association with endometriosis, resistance to oxidative stress, and poor prognosis owing to its resistance to conventional platinum-based chemotherapy. A greater understanding of the molecular characteristics and pathogenesis of ovarian cancer subtypes may facilitate the development of targeted therapeutic strategies, though the mechanism of drug resistance in ovarian CCC has yet to be determined. In this study, we assessed exome sequencing data to identify new therapeutic targets of mitochondrial function in ovarian CCC because of the central role of mitochondria in redox homeostasis. Copy number analyses revealed that chromosome 17q21-24 (chr.17q21-24) amplification was associated with recurrence in ovarian CCC. Cell viability assays identified an association between cisplatin resistance and chr.17q21-24 amplification, and mitochondrion-related genes were enriched in patients with chr.17q21-24 amplification. Patients with high expression of pyruvate dehydrogenase kinase 2 (PDK2) had a worse prognosis than those with low PDK2 expression. Furthermore, inhibition of PDK2 synergistically enhanced cisplatin sensitivity by activating the electron transport chain and by increasing the production of mitochondrial reactive oxygen species. Mouse xenograft models showed that inhibition of PDK2 with cisplatin inhibited tumor growth. This evidence suggests that targeting mitochondrial metabolism and redox homeostasis is an attractive therapeutic strategy for improving drug sensitivity in ovarian CCC.

リンク情報
DOI
https://doi.org/10.1111/cas.15125
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/34464482
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8586679
ID情報
  • DOI : 10.1111/cas.15125
  • PubMed ID : 34464482
  • PubMed Central 記事ID : PMC8586679

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