PXD019728

PXD019728 is an original dataset announced via ProteomeXchange.

Title	Elucidating the role of the kinase activity of endothelial cell focal adhesion kinase in angiocrine signalling and tumour growth
Description	A common limitation of cancer treatments is chemotherapy resistance. We have previously identified a molecular mechanism where chemotherapy resistance is regulated by endothelial cells. Endothelial cell specific knockout of focal adhesion kinase (FAK) sensitises tumour cells to DNA-damaging therapies, reducing tumour growth in mice. Our current study addresses the kinase dependent component of endothelial cell FAK sensitisation to the DNA damaging chemotherapeutic drug doxorubicin. FAK is recognised as a therapeutic target in tumour cells, leading to the development of a range of inhibitors, the majority being ATP competitive kinase inhibitors. We demonstrate that specific inactivation of the FAK kinase domain in endothelial cells of blood vessels in established subcutaneous B16F0 tumours sensitises melanoma cells to doxorubicin. Tumour growth was reduced in response to doxorubicin treatment in FAK kinase-dead but not in wild-type mice. Furthermore, we demonstrate that doxorubicin reduces perivascular proliferation, enhances apoptosis and DNA-damage in endothelial cell FAK kinase dead tumours. When we treated human pulmonary microvascular endothelial cells with the FAK kinase inhibitors defactinib, PF-562,271 and PF-573,228 in combination with doxorubicin, we observed a reduction in cytokine levels, implying a possible mechanism for FAK kinase domain in chemosensitisation. Together, these results confirm the role of the kinase domain of EC-FAK in chemosensitising tumour cells to doxorubicin.
HostingRepository	PRIDE
AnnounceDate	2021-11-02
AnnouncementXML	Submission_2021-11-02_07:12:47.239.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD019728
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Pedro Casado-Izquierdo
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2020-06-11 17:30:06	ID requested
⏵ 1	2021-11-02 07:12:47	announced

Dataset with its publication pending

submitter keyword: FAK, Endothelial Cell, Micro-environment, doxorubicin

Pedro R. Cutillas
contact affiliation	Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary Universty of London
contact email	p.cutillas@qmul.ac.uk
lab head
Pedro Casado-Izquierdo
contact affiliation	Cell Signalling
contact email	p.m.casado-izquierdo@qmul.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD019728
     1. Label: PRIDE project
     2. Name: Elucidating the role of the kinase activity of endothelial cell focal adhesion kinase in angiocrine signalling and tumour growth