SLC6A6 alleviates cellular senescence in glioblastoma via the CSK/AKT/FoxO1 signaling

・Background: Malignant glioblastoma exhibits cellular senescence characterized by changing tumor microenvironment. Solute carrier family 6 member 6 (SLC6A6), a multichannel transmembrane protein, plays a crucial role in regulating cell proliferation, apoptosis, differentiation and cellular microenvironment. However, the molecular mechanism of SLC6A6 in the cellular senescence of glioblastoma remains unknown. Our study aimed to elucidate the regulatory role and molecular mechanisms of SLC6A6 in the proliferation and senescence of glioblastoma cells. ・Methods: Expression of SLC6A6 was examined in tumor samples from 50 patients with glioblastoma, and associations between SLC6A6 expression and survival outcome were evaluated using Kaplan–Meier survival and Cox regression analyses. To investigate the mechanism of SLC6A6, we used short hairpin RNA (shRNA) and overexpression vector to construct SLC6A6-knockdown and -overexpression glioblastoma cells, respectively. The role of SLC6A6 in glioblastoma was confirmed in vitro and in an orthotopic glioblastoma mouse model. ・Results: Patients with high expression of SLC6A6 had a worse prognosis. Downregulation of SLC6A6 protein inhibited malignant phenotypes of glioblastoma cells in vitro. In addition, SLC6A6 affected tumor senescence by directly binding to CSK with its N-terminal cytoplasmic domain, thereby enhancing AKT phosphorylation. Furthermore, SLC6A6 knockdown inhibited tumor growth and shortened survival in the glioblastoma xenograft mouse model. ・Conclusion: SLC6A6 can promote malignant progression and inhibit cellular senescence of glioblastoma cells by affecting the CSK/AKT/FoxO1 signaling pathway. SLC6A6 might be a valuable biomarker in the treatment of glioblastoma.