Chloroquine induces apoptosis in pancreatic neuroendocrine neoplasms via endoplasmic reticulum stress

Kenzo Nakano, Toshihiko Masui, Akitada Yogo, Yuichiro Uchida, Asahi Sato, Yosuke Kasai, Kazuyuki Nagai, Takayuki Anazawa, Yoshiya Kawaguchi, Shinji Uemoto

研究成果: Article査読

1 被引用数 (Scopus)

抄録

Although pancreatic neuroendocrine neoplasms (PanNENs) are generally indolent, patients with distant metastasis have a dismal prognosis. Recently, the autophagy inhibitor chloroquine (CQ) has been shown to suppress the tumour growth of PanNENs, but the detailed mechanisms have not been elucidated. Furthermore, these results were obtained from poorly differentiated cell lines rather than well-differentiated cell lines, which is the most prevalent type in this tumour. To explore the mechanism and efficacy of CQ on PanNENs, we applied CQ to cell lines and evaluated the resulting apoptosis and endoplasmic reticulum (ER) stress. CQ treatment induced ER stress, and an unfolded protein response was activated through the PERK-eIF2α-ATF4 pathway, resulting in the expression of the pro-apoptotic protein C/EBP homologous protein (CHOP), which reflects ER-stress-mediated apoptotic cell death. Furthermore, hydroxychloroquine (HCQ) was effective in Men1 heterozygous-deficient (Men1+/ΔN3-8) mice, a mouse PanNEN model that is considered to correspond to human low-grade PanNEN. HCQ administration decreased tumour size in Men1+/ΔN3-8 mice. In the HCQ group, histological analyses revealed that proliferative activity was unchanged, but apoptosis was accelerated, accompanied by CHOP expression. These results suggest that autophagy inhibition by CQ/HCQ could be used for the treatment of PanNEN, including the well-differentiated type.

本文言語English
ページ(範囲)431-439
ページ数9
ジャーナルEndocrine-Related Cancer
127
7
DOI
出版ステータスPublished - 07-2020
外部発表はい

All Science Journal Classification (ASJC) codes

  • 内分泌学、糖尿病および代謝内科学
  • 腫瘍学
  • 内分泌学
  • 癌研究

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