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

• Published in: Cell death & disease 2019-11, Vol.10 (12), p.876-17, Article 876
• Main Authors: Takeda, Takashi, Komatsu, Masayuki, Chiwaki, Fumiko, Komatsuzaki, Rie, Nakamura, Kanako, Tsuji, Kosuke, Kobayashi, Yusuke, Tominaga, Eiichiro, Ono, Masaya, Banno, Kouji, Aoki, Daisuke, Sasaki, Hiroki
• Format: Article
• Language: English
• Subjects: 13/109; 13/2; 13/31; 13/44; 13/89; 14; 14/63; 38/39; 631/67/1059/602; 631/67/1517/1371; 631/80/82/23; 82/1; 96/95; Antibodies; Apoptosis; Apoptosis - physiology; Autophagy; Biochemistry; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Biomedical and Life Sciences; Cathepsins; Cathepsins - metabolism; Cell Biology; Cell Culture; Cell viability; Cervical cancer; Cervix; Cisplatin; Female; Gene expression; Gene Knockdown Techniques; Golgi apparatus; Golgi Apparatus - genetics; Golgi Apparatus - metabolism; Golgi Apparatus - pathology; Humans; Immunology; Insulin; Insulin-like growth factor II receptors; Life Sciences; Lysosomes - genetics; Lysosomes - metabolism; Lysosomes - pathology; Malignancy; Mannose; Medical prognosis; Middle Aged; Phagocytosis; Protein folding; Reactive oxygen species; Reactive Oxygen Species - metabolism; Receptor, IGF Type 1 - metabolism; Receptor, IGF Type 2 - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Tumor cell lines; Tumor suppressor genes; Up-Regulation; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - metabolism; Uterine Cervical Neoplasms - pathology
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-2117-9

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.