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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Subverted regulation of Nox1 NADPH oxidase-dependent oxidant generation by protein disulfide isomerase A1 in colon carcinoma cells with overactivated KRas

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De Bessa, Tiphany Coralie [1, 2] ; Pagano, Alessandra [2] ; Soares Moretti, Ana Iochabel [1] ; Santos Oliveira, Percillia Victoria [1] ; Mendonca, Samir Andrade [3] ; Kovacic, Herve [2] ; Martins Laurindo, Francisco Rafael [1]
Total Authors: 7
[1] Univ Sao Paulo, Hosp Clin HCFMUSP, Fac Med, Inst Coracao InCor, LIM 64, Sao Paulo, SP - Brazil
[2] Aix Marseille Univ, CNRS, UMR 7051, INP, Inst Neurophysiopathol, Fac Pharm, 27 Blvd Jean Moulin, F-13288 Marseille 5 - France
[3] Univ Sao Paulo, Icesp, Ctr Invest Translac Oncol, Fac Med, Sao Paulo, SP - Brazil
Total Affiliations: 3
Document type: Journal article
Source: CELL DEATH & DISEASE; v. 10, FEB 13 2019.
Web of Science Citations: 2

Protein disulfide isomerases including PDIA1 are implicated in cancer progression, but underlying mechanisms are unclear. PDIA1 is known to support vascular Nox1 NADPH oxidase expression/activation. Since deregulated reactive oxygen species (ROS) production underlies tumor growth, we proposed that PDIA1 is an upstream regulator of tumor-associated ROS. We focused on colorectal cancer (CRC) with distinct KRas activation levels. Analysis of RNAseq databanks and direct validation indicated enhanced PDIA1 expression in CRC with constitutive high (HCT116) vs. moderate (HKE3) and basal (Caco2) Ras activity. PDIA1 supported Nox1-dependent superoxide production in CRC; however, we first reported a dual effect correlated with Ras-level activity: in Caco2 and HKE3 cells, loss-of-function experiments indicate that PDIA1 sustains Nox1-dependent superoxide production, while in HCT116 cells PDIA1 restricted superoxide production, a behavior associated with increased Rac1 expression/activity. Transfection of Rac1G12V active mutant into HKE3 cells induced PDIA1 to become restrictive of Nox1-dependent superoxide, while in HCT116 cells treated with Rac1 inhibitor, PDIA1 became supportive of superoxide. PDIA1 silencing promoted diminished cell proliferation and migration in HKE3, not detectable in HCT116 cells. Screening of cell signaling routes affected by PDIA1 silencing highlighted GSK3 beta and Stat3. Also, E-cadherin expression after PDIA1 silencing was decreased in HCT116, consistent with PDIA1 support of epithelial-mesenchymal transition. Thus, Ras overactivation switches the pattern of PDIA1-dependent Rac1/Nox1 regulation, so that Ras-induced PDIA1 bypass can directly activate Rac1. PDIA1 may be a crucial regulator of redox-dependent adaptive processes related to cancer progression. (AU)

FAPESP's process: 16/00686-8 - Mechanisms underlying the loss of protein disulfide isomerase-dependent regulation of NADPH oxidase in colon carcinoma cells with Ras overactivation
Grantee:Tiphany Coralie de Bessa
Support Opportunities: Scholarships abroad - Research Internship - Doctorate
FAPESP's process: 09/54764-6 - Regulation of redox homeostasis and integrated stress response by Protein Disulfide Isomerase (PDI): mechanisms and role in the pathophysiology and therapy of vascular diseases
Grantee:Francisco Rafael Martins Laurindo
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 14/20595-1 - Protein Disulfide Isomerase (PDI) as a marker of risk for thrombosis and/or accelerated progression of atherosclerosis in patients with familial hipercholesterolemia and in experimental model
Grantee:Percíllia Victória Santos de Oliveira
Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
FAPESP's process: 13/02070-6 - Mechanisms associated with loss of regulation of NADPH oxidase Nox1 by protein disulfide isomerase in cells with sustained activation of the Ras pathway
Grantee:Tiphany Coralie de Bessa
Support Opportunities: Scholarships in Brazil - Doctorate
FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
Grantee:Ohara Augusto
Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC