GABARAP suppresses EMT and breast cancer progression via the AKT/mTOR signaling pathway

Background Triosephosphate isomerase 1 (TPI1), as a key glycolytic enzyme, is upregulated in multiple cancers. However, expression profile and regulatory mechanism of TPI1 in breast cancer (BRCA) remain mysterious. Methods Western blotting and immunohistochemistry (IHC) assays were used to investigate the expression of TPI1 in BRCA specimens and cell lines. TPI1 correlation with the clinicopathological characteristics and prognosis of 362 BRCA patients was analyzed using a tissue microarray. Overexpression and knockdown function experiments in cells and mice models were performed to elucidate the function and mechanisms of TPI1-induced BRCA progression. Related molecular mechanisms were clarified using co-IP, IF, mass spectrometric analysis, and ubiquitination assay. Results We have found TPI1 is highly expressed in BRCA tissue and cell lines, acting as an independent indicator for prognosis in BRCA patients. TPI1 promotes BRCA cell glycolysis, proliferation and metastasis in vitro and in vivo. Mechanistically, TPI1 activates phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway to regulate epithelial–mesenchymal transformation (EMT) and aerobic glycolysis, which is positively mediated by cell division cycle associated 5 (CDCA5). Moreover, TPI1 interacts with sequestosome-1 (SQSTM1)/P62, and P62 decreases the protein expression of TPI1 by promoting its ubiquitination in MDA-MB-231 cells. Conclusions TPI1 promotes BRCA progression by stabilizing CDCA5, which then activates the PI3K/AKT/mTOR pathway. P62 promotes ubiquitin-dependent proteasome degradation of TPI1. Collectively, TPI1 promotes tumor development and progression, which may serve as a therapeutic target for BRCA.

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“…The IHC assay was performed as previously described [ 25 ]. Primary antibodies were listed in an Additional file 1 : Table S1.…”

Section: Methodsmentioning

confidence: 99%

“…WB was conducted as previously described [ 25 ]. Briefly, cell lysates were obtained using RIPA lysis buffer (Beyotime, Shanghai, China).…”

Section: Methodsmentioning

confidence: 99%

TPI1 activates the PI3K/AKT/mTOR signaling pathway to induce breast cancer progression by stabilizing CDCA5

et al. 2022

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“…In vitro studies have shown that this is mostly due to their involvement in the selective degradation of several oncogenic proteins, as described for the LC3-mediated degradation of SNAI1 [20,30,51,52]. However, the ATG8 proteins might also be involved in cancer inhibition in a selective-autophagy-independent pathway, via the regulation of several signaling pathways involved in cancer progression [40,53].…”

Section: Discussionmentioning

confidence: 99%

GABARAPL1 Inhibits EMT Signaling through SMAD-Tageted Negative Feedback

Jacquet

Hervouet

Baudu

et al. 2021

Biology

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The pathway of selective autophagy, leading to a targeted elimination of specific intracellular components, is mediated by the ATG8 proteins, and has been previously suggested to be involved in the regulation of the Epithelial–mesenchymal transition (EMT) during cancer’s etiology. However, the molecular factors and steps of selective autophagy occurring during EMT remain unclear. We therefore analyzed a cohort of lung adenocarcinoma tumors using transcriptome analysis and immunohistochemistry, and found that the expression of ATG8 genes is correlated with that of EMT-related genes, and that GABARAPL1 protein levels are increased in EMT+ tumors compared to EMT- ones. Similarly, the induction of EMT in the A549 lung adenocarcinoma cell line using TGF-β/TNF-α led to a high increase in GABARAPL1 expression mediated by the EMT-related transcription factors of the SMAD family, whereas the other ATG8 genes were less modified. To determine the role of GABARAPL1 during EMT, we used the CRISPR/Cas9 technology in A549 and ACHN kidney adenocarcinoma cell lines to deplete GABARAPL1. We then observed that GABARAPL1 knockout induced EMT linked to a defect of GABARAPL1-mediated degradation of the SMAD proteins. These findings suggest that, during EMT, GABARAPL1 might intervene in an EMT-regulatory loop. Indeed, induction of EMT led to an increase in GABARAPL1 levels through the activation of the SMAD signaling pathway, and then GABARAPL1 induced the autophagy-selective degradation of SMAD proteins, leading to EMT inhibition.

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“… 26 But another study result suggested that GABARAP can suppress progression of breast cancer. 27 , 28 GABARAP expresses differently between Glioma and normal brain tissue and has a prognostic value in Glioma patient. 29 GABARAP has a relation with tumorigenesis of melanoma and ablation of GABARAP in mice suppresses tumor growth.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatic Analysis of Prognostic Value of Pyroptosis-Related Genes and Its Effect on Immune Cell Infiltration in Pancreatic Adenocarcinoma

Wang¹,

Zhang²,

Shao³

et al. 2022

IJGM

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Purpose Pancreatic adenocarcinoma has a poor prognosis and chemotherapy has its limitation due to tumor heterogeneity. It is essential to find novel targets involving in tumorigenesis of pancreatic adenocarcinoma. Growing evidences indicated that pyroptosis is involved in tumorigenesis of many cancers, but the relationship between pyroptosis and pancreatic adenocarcinoma still remains to be elucidated. Our object is to explore whether pyroptosis-related different expression genes have association with survivals of pancreatic adenocarcinoma patients and the mechanism they may participate in. Besides, we also analyzed their effect on immune cell infiltration in tumor microenvironment. Patients and Methods We used the bioinformatic analysis tool including GEPIA, cBioPortal, STRING, GeneMANIA, R software 4.03 and TIMER2.0 to investigate the different expression, prognostic value, protein-protein interaction, gene ontology, pathway and effect of immune cell infiltration of pyroptosis-related genes in PAAD. Results Many pyroptosis-related genes express differently between pancreatic adenocarcinoma and normal tissues and they are associated with survival of PAAD. GABARAP and IL18 may play a key role in tumorigenesis of PAAD, for they are connected with overall survival, disease free survival and pathological stages at the same time. The function of pyroptosis-related genes includes cytokine production, endopeptidase activity, regulation of inflammation and inflammasome complex and pyroptosis-related genes have effect on immune cells infiltration in PAAD microenvironment. Conclusion Lots of pyroptosis-related DEGs may get involved in pathogenesis of PAAD and their high expression have an effect on survival. GABARAP and IL18 could be valuable research targets of PAAD.

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GABARAP suppresses EMT and breast cancer progression via the AKT/mTOR signaling pathway

Cited by 19 publications

References 42 publications

TPI1 activates the PI3K/AKT/mTOR signaling pathway to induce breast cancer progression by stabilizing CDCA5

TPI1 activates the PI3K/AKT/mTOR signaling pathway to induce breast cancer progression by stabilizing CDCA5

GABARAPL1 Inhibits EMT Signaling through SMAD-Tageted Negative Feedback

Bioinformatic Analysis of Prognostic Value of Pyroptosis-Related Genes and Its Effect on Immune Cell Infiltration in Pancreatic Adenocarcinoma

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