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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Article number876
JournalCell Death and Disease
Volume10
Issue number12
DOIs
Publication statusPublished - 2019 Dec 1

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Somatomedin Receptors
Cathepsins
Uterine Cervical Neoplasms
Up-Regulation
Apoptosis
Mitochondrial Degradation
IGF Type 2 Receptor
Proteins
Insulin-Like Growth Factor II
Autophagy
Gene Expression Profiling
Lysosomes
Tumor Suppressor Genes
Cisplatin
Reactive Oxygen Species
Cell Survival
Survival Rate
Biomarkers
Ligands
Cell Line

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

Upregulation of IGF2R evades lysosomal dysfunction-induced apoptosis of cervical cancer cells via transport of cathepsins. / Takeda, Takashi; Komatsu, Masayuki; Chiwaki, Fumiko; Komatsuzaki, Rie; Nakamura, Kanako; Tsuji, Kosuke; Kobayashi, Yusuke; Tominaga, Eiichiro; Ono, Masaya; Banno, Kouji; Aoki, Daisuke; Sasaki, Hiroki.

In: Cell Death and Disease, Vol. 10, No. 12, 876, 01.12.2019.

Research output: Contribution to journalArticle

Takeda, Takashi ; Komatsu, Masayuki ; Chiwaki, Fumiko ; Komatsuzaki, Rie ; Nakamura, Kanako ; Tsuji, Kosuke ; Kobayashi, Yusuke ; Tominaga, Eiichiro ; Ono, Masaya ; Banno, Kouji ; Aoki, Daisuke ; Sasaki, Hiroki. / Upregulation of IGF2R evades lysosomal dysfunction-induced apoptosis of cervical cancer cells via transport of cathepsins. In: Cell Death and Disease. 2019 ; Vol. 10, No. 12.
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