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Cited by 60Autophagy in Disease and TherapyCellular transport and secretionGrowth Hormone and Insulin-like Growth Factors

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

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Takeda, Takashi, Komatsu, Masayuki, Chiwaki, Fumiko, Komatsuzaki, Rie, Nakamura, Kanako, Tsuji, Kosuke, Kobayashi, Yusuke, Tominaga, Eiichiro, Ono, Masaya, Banno, Kouji, Aoki, Daisuke, Sasaki, Hiroki·2019·Cell Death & Disease
DOI 10.1038/s41419-019-2117-9PMC PMC6868013
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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.

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  • CI-M6PR (IGF2R) binds M6P-labelled cargo and has a central role in trafficking cathepsins to lysosomes.

    “One possible candidate is the cation-independent mannose-6-phosphate receptor (CI-M6PR, also known as IGF2R), which binds M6P-labelled cargo and has a central role in trafficking cathepsins to lysosomes 44 .”

    From Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover (2026) · cites this paper as [44]

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Metadata

Authors
Takeda, T., Komatsu, M., Chiwaki, F., Komatsuzaki, R., Nakamura, K., Tsuji, K., Kobayashi, Y., Tominaga, E., Ono, M., Banno, K., Aoki, D., & Sasaki, H.
Affiliations
  • Keio University (JP)
  • National Cancer Center Research Institute (JP)
Corresponding author
  • Komatsu, Masayuki
  • Sasaki, Hiroki
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2019-11-20
Volume
10
Issue
12
Pages
876-876
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/s41419-019-2117-9
PMC
PMC6868013
OpenAlex
W2991407782
Cited by
60
References
1
Citations by year
2026: 8 · 2025: 7 · 2024: 10 · 2023: 10 · 2022: 11 · 2021: 11 · 2020: 3
FWCI
4.66
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Disease (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Keio University
  • Japan Society for the Promotion of Science (18K16812, 18H03330, 17H06419, 18K09298, 19K22892)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
Keywords
IGF2R, cervical cancer, lysosomal dysfunction, cathepsins, mannose 6-phosphate receptor, apoptosis, autophagy, mitophagy, cisplatin sensitivity, IGF1R signaling, oncogenic role, prognostic factors, misfolded protein accumulation, reactive oxygen species
MeSH terms
Cathepsins, Uterine Cervical Neoplasms, Female, Golgi Apparatus, Humans, Lysosomes, Middle Aged, RNA, Messenger, Biomarkers, Tumor, Up-Regulation, Apoptosis, Reactive Oxygen Species, Receptor, IGF Type 1, Receptor, IGF Type 2, Gene Knockdown Techniques

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