mTORC1-independent autophagy regulates receptor tyrosine kinase phosphorylation in colorectal cancer cells via an mTORC2-mediated mechanism

Lampada, Aikaterini; O’Prey, Jim; Szabadkai, György; Ryan, Kevin M.; Hochhauser, Daniel; Salomoni, Paolo

doi:10.1038/cdd.2017.41

Cited by 59 publications

(55 citation statements)

References 89 publications

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“…Immunofluorescence of primary chordoma cells was performed as described previously (45) using antibodies listed in Table S3. CRISPR/Cas9 knockdown.…”

Section: Methodsmentioning

confidence: 99%

Epigenetic inactivation of oncogenic brachyury (TBXT) by H3K27 histone demethylase controls chordoma cell survival

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Hookway

Cribbs

et al. 2018

Preprint

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Equal contribution Corresponding authors Adrienne M Flanagan, a.flanagan@ucl.ac.uk, Telephone +44 (0) 20 7679 6304 and Udo Oppermann, udo.oppermann@sgc.ox.ac.uk, Telephone +44 (0) 1865 227308 2 2 AbstractThe expression of the transcription factor brachyury (TBXT) is normally restricted to embryonic development and its silencing after mesoderm development is epigenetically regulated. In chordoma, a rare tumour of notochordal differentiation, TBXT acts as a putative oncogene, and we hypothesised that its expression could be controlled through epigenetic inhibition. Screening of five chordoma cell lines revealed that only inhibitors of the histone 3 lysine 27 demethylases KDM6A (UTX) and KDM6B (Jmjd3) reduce TBXT expression and lead to cell death, findings validated in primary patient-derived culture systems. Pharmacological inhibition of KDM6 demethylases leads to genome-wide increases in repressive H3K27me3 marks, accompanied by significantly reduced TBXT expression, an effect that is phenocopied by the dual genetic inactivation of KDM6A/B using CRISPR/Cas9. Transcriptional profiles in response to a novel KDM6A/B inhibitor, KDOBA67, revealed downregulation of critical genes and transcription factor networks for chordoma survival pathways, whereas upregulated pathways were dominated by stress, cell cycle and pro-apoptotic response pathways.This study supports previous data showing that the function of TBXT is essential for maintaining notochord cell fate and function and provides further evidence that TBXT is an oncogenic driver in chordoma. Moreover, the data suggest that TBXT can potentially be targeted therapeutically by modulating epigenetic control mechanisms such as H3K27 demethylases.3 3

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“…Immunofluorescence of primary chordoma cells was performed as described previously (45) using antibodies listed in Table S3. CRISPR/Cas9 knockdown.…”

Section: Methodsmentioning

confidence: 99%

Epigenetic inactivation of oncogenic brachyury (TBXT) by H3K27 histone demethylase controls chordoma cell survival

Cottone

Hookway

Cribbs

et al. 2018

Preprint

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“…In addition, RICTOR could directly activate many downstream molecules. For instance, RICTOR directly phosphorylates the downstream molecule PKCα and inhibits RhoGDI2 (inhibitor of Rac), resulting in the upregulation of RAC1 expression, which enhances chemotaxis and metastatic ability of the cell (Morrison Joly et al 2017); RICTOR could influence the level of p-c-MET instead of the total level of c-MET to modulate autophagy (Lampada et al 2017); RICTOR could regulate the expression of HIF-1α and increases the secretion of hypoxia-induced VEGF-A and constitutive IL-8 in response to a hypoxic environment (Schmidt et al 2017). These processes are impaired by RICTOR elimination and increased by RICTOR overexpression.…”

Section: Akt-independent Mechanismsmentioning

confidence: 99%

The role of RICTOR amplification in targeted therapy and drug resistance

Zhao

Jiang

Zhang

2020

Mol Med

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The emergence of tyrosine kinase inhibitors (TKIs) has changed the current treatment paradigm and achieved good results in recent decades. However, an increasing number of studies have indicated that the complex network of receptor tyrosine kinase (RTK) co-activation could influence the characteristic phenotypes of cancer and the tumor response to targeted treatments. One of strategies to blocking RTK co-activation is targeting the downstream factors of RTK, such as PI3K-AKT-mTOR pathway. RICTOR, a core component of mTORC2, acts as a key effector molecule of the PI3K-AKT pathway; its amplification is often associated with poor clinical outcomes and resistance to TKIs. Here, we discuss the biology of RICTOR in tumor and the prospects of targeting RICTOR as a complementary therapy to inhibit RTK coactivation.

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“…Recent findings have suggested a role for autophagy in the control of cell signalling and protein phosphorylation. [2][3][4][5] Our group has recently established a novel role of basal autophagy in regulation of RTK phosphorylation in colorectal cancer cell lines. Specifically, mTORC1-independent basal autophagy was found to positively modulate phosphorylation levels of several RTKs, such as c-MET, c-RET and Dtk.…”

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confidence: 99%

“…Specifically, genetic inhibition of mTORC2 as well as pharmacological inhibition of both mTORC1/2 led to decreased c-MET phosphorylation in autophagy proficient but not autophagy-impaired cells. 3 Recently, a non-canonical autophagy pathway was found to regulate intracellular c-MET signalling in breast and lung cancer cell lines upon detachment, following HGF stimulation. However, in these settings genetic suppression of autophagy genes did not affect c-MET phosphorylation.…”

mentioning

confidence: 99%

“…Therefore, autophagic-like vesicles may represent signalling platforms whereby c-MET phosphorylation is controlled through mTORC2. 3 Interestingly, two recent studies demonstrated that mTORC2 kinase activity is associated with intracellular membrane compartments and regulation of AKT inside the cell. 6,7 Ebner et al, observed endogenous mTORC2 activity at the plasma membrane as well as at intracellular compartments such as outer mitochondrial membranes, and a subpopulation of early and late endosomes.…”

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confidence: 99%

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