Upregulation of IGF2R evades lysosomal dysfunction-induced apoptosis of cervical cancer cells via transport of cathepsins

Takashi Takeda, Masayuki Komatsu, Fumiko Chiwaki, Rie Komatsuzaki, Kanako Nakamura, Kosuke Tsuji, Yusuke Kobayashi, Eiichiro Tominaga, Masaya Ono, Kouji Banno, Daisuke Aoki, Hiroki Sasaki

研究成果: Article査読

7 被引用数 (Scopus)

抄録

Cervical cancer is the most common gynecological malignancy in the world; however, the survival rates of advanced-stage and recurrent cervical cancer patients remain poor. The multifaced protein insulin-like growth factor 2 receptor (IGF2R) has various ligands, represented as IGF-2 and mannose-6-phosphate (M6P)-tagged proteins. Regarding its antagonistic activity as an IGF1R signal, IGF2R is currently considered a tumor suppressor gene, whereas its significance as an M6P receptor is still unclear. Here, on the basis of transcriptome analysis of TCGA and GEO open datasets, we show that IGF2R is upregulated and correlated with poor prognosis in cervical cancer. Several experiments using cervical cancer cell lines revealed that IGF2R depletion induced apoptosis, decreased cell viability, and increased vulnerability to certain anticancer drug cisplatin. In contrast to its negligible impact in IGF1R signaling, loss of IGF2R disrupted the Golgi-to-lysosome transport of M6P-tagged cathepsins, resulting in decreased lysosomal activity, with their abnormal accumulation and dysfunction of both autophagy and mitophagy, which cause the accumulation of misfolded proteins and production of reactive oxygen species. Taken together, IGF2R has an oncogenic role through transportation of M6P-tagged cargo in cervical cancer and can be used as a predictive biomarker for prognostic classification.

本文言語English
論文番号876
ジャーナルCell Death and Disease
10
12
DOI
出版ステータスPublished - 2019 12 1

ASJC Scopus subject areas

  • 免疫学
  • 細胞および分子神経科学
  • 細胞生物学
  • 癌研究

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