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

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 A 1 : bafilomycin A 1 ; 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

Loss of the adaptor protein Sh3bgrl initiates ovarian fibrosis in zebrafish

“…As an adaptor protein, how Sh3bgrl regulates ECM-and fiber-related genes should be further characterized. It was shown that Sh3bgrl regulates robotic gene expression by binding with various ribosome components in human tumor cells [2,4], which would be confirmed in our zebrafish systems.…”

“…SH3BGRL is broadly expressed in many human tissues and organs, including bone marrow, heart, liver, and kidneys [31]. Recently, it is shown that SH3BGRL is associated with some human diseases, including acute myeloid leukemia (AML) [32], neurodegenerative disease [33], and breast cancer [2][3][4]. However, little is known about the relationship between SH3BGRL and female infertility.…”

“…However, little is known about its physiological roles in organism development. Recently, our studies showed that SH3BGRL is associated with tumor progression and drug resistance [2][3][4], but these are limited to the cellular level. There is no animal model to dissect the biological function of SH3BGRL during development and diseases.…”

FGF19 promotes cell autophagy and cisplatin chemoresistance by activating MAPK signaling in ovarian cancer

“…In gastric cancer, Zinc oxide nanoparticle (ZnO-NP) alleviates the chemoresistance by inhibiting autophagy ( Miao et al, 2021 ). Abnormally expressed SH3BGRL could drive the chemotherapy resistance through enhancing cell autophagy in breast cancer ( Zhang et al, 2022b ).…”

The dual role of autophagy in the regulation of cancer treatment

“…Zhang et al have proven in breast cancer that adaptor SH3BGRL can potentiate autophagy-induced doxorubicin resistance by promoting PIK3C3 translation and ATG12 stability. Furthermore, the genetic knockdown of either PIK3C3 or ATG12 attenuated autophagy and re-sensitized breast cancer cells to doxorubicin (Zhang et al 2022 ). A mechanistic study has revealed that ecotropic viral integration site 1 (EVI1) upregulates ATG7 expression to impede the sensitivity of leukemia cells to imatinib treatment (Niu et al 2020 ).…”