Biallelic loss of FAM46C triggers tumor growth with concomitant activation of Akt signaling in multiple myeloma cells
| Autor: | Jo Kanasugi, Shohei Mizuno, Wahiduzzaman, Yoshitaka Hosokawa, Akinobu Ota, Akiyoshi Takami, Hiroyuki Konishi, Ichiro Hanamura, Vu Quang Lam, Lutfur Rahman, Toshinori Hyodo, Shinobu Tsuzuki, Sivasundaram Karnan |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Cell signaling tumor suppressor Carcinogenesis Cell Survival Antineoplastic Agents Mice SCID Thiophenes Bortezomib 03 medical and health sciences Gene Knockout Techniques Mice Phosphatidylinositol 3-Kinases 0302 clinical medicine Cell Molecular and Stem Cell Biology Cell Line Tumor Tensin PTEN Animals Humans FAM46C Phosphorylation Protein kinase B PI3K/AKT/mTOR pathway biology Chemistry Cell growth PI3K‐Akt Cell Cycle General Medicine Afuresertib Original Articles Nucleotidyltransferases multiple myeloma Gene Expression Regulation Neoplastic tumorigenesis 030104 developmental biology Oncology Cell culture 030220 oncology & carcinogenesis Cancer research biology.protein Pyrazoles Original Article Female Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Cancer Science |
| ISSN: | 1349-7006 1347-9032 |
| Popis: | Loss of heterozygosity or mutation of the family with sequence similarity 46, member C (FAM46C) gene on chromosome band 1p12 is associated with shorter overall survival of patients with multiple myeloma (MM). In this study, using human MM cell lines (KMS‐11, OCI‐My5, and ANBL‐6), we generated FAM46C−/− cell clones and examined the effect of disruption of FAM46C on cell survival and cellular signaling. Cell proliferation assays showed increased clonogenicity of FAM46C−/− KMS‐11 cells compared to WT cells. Xenograft experiments showed significantly shorter overall survival of mice harboring the FAM46C−/− cell‐derived tumors than mice with the FAM46CWT cell‐derived tumors. Notably, levels of phosphorylated Akt and its substrates increased both in vitro and in vivo in the FAM46C−/− cells compared to WT cells. In addition, caspase activities decreased in the FAM46C−/− cells. Results of gene set enrichment analysis showed that loss of FAM46C significantly activated serum‐responsive genes while inactivating phosphatase and tensin homolog (PTEN)‐related genes. Mechanistically, loss of FAM46C decreased the PTEN activity, number of apoptotic cells, and caspase activities. PF‐04691502, a selective PI3K inhibitor, suppressed the augmented phosphorylation of Akt and its substrate FoxO3a. Treatment with afuresertib (a specific Akt inhibitor) in combination with bortezomib additively decreased FAM46C−/− MM cell survival. Collectively, this study is the first to report that loss of FAM46C triggers the concomitant activation of the PI3K‐Akt signaling pathway, which might be a therapeutic target for MM with abnormalities in the FAM46C gene. This study shows, for the first time, that FAM46C loss promotes the PI3K‐Akt signaling pathway in multiple myeloma cells. Notably, loss of FAM46C sensitized cells to specific inhibitor of PI3K‐Akt, afuresertib. |
| Databáze: | OpenAIRE |
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