論文

査読有り 国際誌
2020年7月31日

Androgen Receptor Signaling Reduces the Efficacy of Bacillus Calmette-Guérin Therapy for Bladder Cancer via Modulating Rab27b-induced Exocytosis.

Molecular cancer therapeutics
  • Taichi Mizushima
  • ,
  • Guiyang Jiang
  • ,
  • Takashi Kawahara
  • ,
  • Peng Li
  • ,
  • Bin Han
  • ,
  • Satoshi Inoue
  • ,
  • Hiroki Ide
  • ,
  • Ikuma Kato
  • ,
  • Mehrsa Jalalizadeh
  • ,
  • Etsuko Miyagi
  • ,
  • Mitsunori Fukuda
  • ,
  • Leonardo O Reis
  • ,
  • Hiroshi Miyamoto

記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1158/1535-7163.MCT-20-0050

Although intravesical BCG immunotherapy has been the gold standard for non-surgical management of non-muscle-invasive bladder cancer (BC), a considerable number of patients exhibit resistance to the adjuvant treatment with unexplained mechanisms. This study aimed to investigate whether and how androgen receptor (AR) signals modulate BCG cytotoxicity in BC. AR knockdown or overexpression in BC lines resulted in induction or reduction, respectively, in intracellular BCG quantity and its cytotoxic activity. Microarray screening identified Rab27b, a small GTPase known to mediate bacterial exocytosis, which was up-regulated in BCG-resistant cells and down-regulated in AR-shRNA cells. Knockdown of Rab27b or its effector SYTL3, or overexpression of Rab27b also induced or reduced, respectively, BCG quantity and cytotoxicity. Additionally, treatment with GW4869, which was previously shown to inhibit Rab27b-dependent secretion, induced them and reduced Rab27b expression in BC cells. Meanwhile, AR expression was up-regulated in BCG-resistant lines, compared with respective controls. In a mouse orthotopic xenograft model, Rab27b/SYTL3 knockdown or GW4869 treatment enhanced the amount of BCG within tumors and its suppressive effect on tumor growth. Moreover, in non-muscle-invasive BC specimens from patients subsequently undergoing BCG therapy, positivity of AR/Rab27b expression was associated with significantly higher risks of tumor recurrence. AR activation thus correlates with resistance to BCG treatment, presumably via up-regulating Rab27b expression. Mechanistically, it is suggested that BCG elimination from urothelial cells is induced by Rab27b/SYTL3-mediated exocytosis. Accordingly, Rab27b inactivation, potentially via anti-androgenic drugs, and/or exocytosis inhibition are anticipated to sensitize the efficacy of BCG therapy, especially in patients with BCG-refractory AR/Rab27b-positive BC.

リンク情報
DOI
https://doi.org/10.1158/1535-7163.MCT-20-0050
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/32737155

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