Dataset Information

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

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.

SUBMITTER: Takeda T

PROVIDER: S-EPMC6868013 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Takeda Takashi T Komatsu Masayuki M Chiwaki Fumiko F Komatsuzaki Rie R Nakamura Kanako K Tsuji Kosuke K Kobayashi Yusuke Y Tominaga Eiichiro E Ono Masaya M Banno Kouji K Aoki Daisuke D Sasaki Hiroki H

Cell death & disease 20191120 12

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 unclea ...[more]

PMID: 31748500

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Project description:Recently, we reported that increased expression of CASP9 pro-domain, at the endosomal membrane in response to HSP90 inhibition, mediates a cell-protective effect that does not involve CASP9 apoptotic activity. We report here that a non-apoptotic activity of endosomal membrane CASP9 facilitates the retrograde transport of IGF2R/CI-MPR from the endosomes to the trans-Golgi network, indicating the involvement of CASP9 in endosomal sorting and lysosomal biogenesis. CASP9-deficient cells demonstrate the missorting of CTSD (cathepsin D) and other acid hydrolases, accumulation of late endosomes, and reduced degradation of bafilomycin A1-sensitive proteins. In the absence of CASP9, IGF2R undergoes significant degradation, and its rescue is achieved by the re-expression of a non-catalytic CASP9 mutant. This endosomal activity of CASP9 is potentially mediated by herein newly identified interactions of CASP9 with the components of the endosomal membrane transport complexes. These endosomal complexes include the retromer VPS35 and the SNX dimers, SNX1-SNX5 and SNX2-SNX6, which are involved in the IGF2R retrieval mechanism. Additionally, CASP9 interacts with HGS/HRS/ESCRT-0 and the CLTC (clathrin heavy chain) that participate in the initiation of the endosomal ESCRT degradation pathway. We propose that endosomal CASP9 inhibits the endosomal membrane degradative subdomain(s) from initiating the ESCRT-mediated degradation of IGF2R, allowing its retrieval to transport-designated endosomal membrane subdomain(s). These findings are the first to identify a cell survival, non-apoptotic function for CASP9 at the endosomal membrane, a site distinctly removed from the cytoplasmic apoptosome. Via its non-apoptotic endosomal function, CASP9 impacts the retrograde transport of IGF2R and, consequently, lysosomal biogenesis.Abbreviations: ACTB: actin beta; ATG7: autophagy related 7; BafA1: bafilomycin A1; CASP: caspase; CLTC/CHC: clathrin, heavy chain; CTSD: cathepsin D; ESCRT: endosomal sorting complexes required for transport; HEXB: hexosaminidase subunit beta; HGS/HRS/ESCRT-0: hepatocyte growth factor-regulated tyrosine kinase substrate; IGF2R/CI-MPR: insulin like growth factor 2 receptor; ILV: intraluminal vesicles; KD: knockdown; KO: knockout; M6PR/CD-MPR: mannose-6-phosphate receptor, cation dependent; MEF: murine embryonic fibroblasts; MWU: Mann-Whitney U test; PepA: pepstatin A; RAB7A: RAB7, member RAS oncogene family; SNX-BAR: sorting nexin dimers with a Bin/Amphiphysin/Rvs (BAR) domain each; TGN: trans-Golgi network; TUBB: tubulin beta; VPS26: VPS26 retromer complex component; VPS29: VPS29 retromer complex component; VPS35: VPS35 retromer complex component.

Dataset Information

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

Publications

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

Similar Datasets

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