title: SLC9A3R1 stimulates autophagy via BECN1 stabilization in breast cancer cells.
abstract: Autophagy, a self-catabolic process, has been found to be involved in abrogating the proliferation and metastasis of breast cancer. SLC9A3R1 (solute carrier family 9, subfamily A [NHE3, cation proton antiporter 3], member 3 regulator 1), a multifunctional scaffold protein, is involved in suppressing breast cancer cells proliferation and the SLC9A3R1-related signaling pathway regulates the activation of autophagy processes. However, the precise regulatory mechanism and signaling pathway of SLC9A3R1 in the regulation of autophagy processes in breast cancer cells remains unknown. Here, we report that the stability of BECN1, the major component of the autophagic core lipid kinase complex, is augmented in SLC9A3R1-overexpressing breast cancer MDA-MB-231 cells, subsequently stimulating autophagy by attenuating the interaction between BECN1 and BCL2. Initially, we found that SLC9A3R1 partially stimulated autophagy through the PTEN-PI3K-AKT1 signaling cascade in MDA-MB-231 cells. SLC9A3R1 then attenuated the interaction between BECN1 and BCL2 to stimulate the autophagic core lipid kinase complex. Further findings revealed that SLC9A3R1 bound to BECN1 and subsequently blocked ubiquitin-dependent BECN1 degradation. And the deletion of the C-terminal domain of SLC9A3R1 resulted in significantly reduced binding to BECN1. Moreover, the lack of C-terminal of SLC9A3R1 neither reduced the ubiquitination of BECN1 nor induced autophagy in breast cancer cells. The decrease in BECN1 degradation induced by SLC9A3R1 resulted in the activity of autophagy stimulation in breast cancer cells. These findings indicate that the SLC9A3R1-BECN1 signaling pathway participates in the activation of autophagy processes in breast cancer cells.
authors.affiliation: a Department of Oncology ; Institute of Medicinal Biotechnology; Peking Union Medical College; Chinese Academy of Medical Sciences ; Beijing , China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: a Department of Oncology ; Institute of Medicinal Biotechnology; Peking Union Medical College; Chinese Academy of Medical Sciences ; Beijing , China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ma
authors.affiliation: a Department of Oncology ; Institute of Medicinal Biotechnology; Peking Union Medical College; Chinese Academy of Medical Sciences ; Beijing , China.
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: He
authors.affiliation: b China Astronaut Research and Training Center ; Beijing , China.
authors.forename: Jia-Ping
authors.initials: JP
authors.lastname: Wang
authors.affiliation: a Department of Oncology ; Institute of Medicinal Biotechnology; Peking Union Medical College; Chinese Academy of Medical Sciences ; Beijing , China.
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Jiang
authors.affiliation: a Department of Oncology ; Institute of Medicinal Biotechnology; Peking Union Medical College; Chinese Academy of Medical Sciences ; Beijing , China.
authors.forename: Rong-Guang
authors.initials: RG
authors.lastname: Shao
mesh_terms: D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D010750:Phosphoproteins; D017923:Sodium-Hydrogen Exchangers; D025801:Ubiquitin; C093376:sodium-hydrogen exchanger regulatory factor
keywords: SLC9A3R1 signaling pathway, stimulating autophagy; breast cancer cells; protein interaction; protein stability; ubiquitination degradation