2. Academic Validation
  3. Adaptor SH3BGRL drives autophagy-mediated chemoresistance through promoting PIK3C3 translation and ATG12 stability in breast cancers

Adaptor SH3BGRL drives autophagy-mediated chemoresistance through promoting PIK3C3 translation and ATG12 stability in breast cancers

  • Autophagy. 2022 Aug;18(8):1822-1840. doi: 10.1080/15548627.2021.2002108.
Shaoyang Zhang 1 2,  Xiufeng Liu 1 2,  Saleh Abdulmomen Ali Mohammed 2,  Hui Li 3,  Wanhua Cai 2,  Wen Guan 4,  Daiyun Liu 2,  Yanli Wei 2,  Dade Rong 2,  Ying Fang 2,  Farhan Haider 2,  Haimei Lv 1,  Ziwei Jin 1 2,  Xiaomin Chen 5,  Zhuomao Mo 6,  Lujie Li 2,  Shulan Yang 1,  Haihe Wang 2 6
Affiliations

Affiliations

  • 1 Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 2 Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • 3 Reproductive Medical Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 4 Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China.
  • 5 Department of Hematology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 6 Center for Stem Cell Biology and Tissue Engineering, Key Laboratory of Ministry of Education, Sun Yat-sen University, Guangzhou, China.
PMID: 34870550 DOI: 10.1080/15548627.2021.2002108
Abstract

Acquired chemotherapy resistance is one of the main culprits in the relapse of breast Cancer. But the underlying mechanism of chemotherapy resistance remains elusive. Here, we demonstrate that a small adaptor protein, SH3BGRL, is not only elevated in the majority of breast Cancer patients but also has relevance with the relapse and poor prognosis of breast Cancer patients. Functionally, SH3BGRL upregulation enhances the chemoresistance of breast Cancer cells to the first-line doxorubicin treatment through macroautophagic/autophagic protection. Mechanistically, SH3BGRL can unexpectedly bind to ribosomal subunits to enhance PIK3C3 translation efficiency and sustain ATG12 stability. Therefore, inhibition of Autophagy or silence of PIK3C3 or ATG12 can effectively block the driving effect of SH3BGRL on doxorubicin resistance of breast Cancer cells in vitro and in vivo. We also validate that SH3BGRL expression is positively correlated with that of PIK3C3 or ATG12, as well as the constitutive occurrence of Autophagy in clinical breast Cancer tissues. Taken together, our data reveal that SH3BGRL upregulation would be a key driver to the acquired chemotherapy resistance through Autophagy enhancement in breast Cancer while targeting SH3BGRL could be a potential therapeutic strategy against breast Cancer.Abbreviations: ABCs: ATP-binding cassette transporters; Act D: actinomycin D; ACTB/β-actin: actin beta; ATG: autophagy-related; Baf A1: bafilomycin A1; CASP3: Caspase 3; CHX: cycloheximide; CQ: chloroquine; Dox: doxorubicin; FBS: fetal bovine serum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GEO: gene expression omnibus; GFP: green fluorescent protein; G6PD: glucose-6-phosphate dehydrogenase; GSEA: gene set enrichment analysis; IHC: immunochemistry; KEGG: Kyoto Encyclopedia of Genes and Genomes; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; 3-MA: 3-methyladenine; mRNA: messenger RNA; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; SH3BGRL: SH3 domain binding glutamate-rich protein-like; SQSTM1/p62: sequestosome 1; ULK1: unc-51 like Autophagy activating kinase 1.

Keywords

ATG12; PIK3C3; SH3BGRL; autophagy; breast cancer; doxorubicin chemoresistance; polyribosome profile; protein stability; ribosome-binding protein.

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