N-WASP attenuates cell proliferation and migration through ERK2-dependent enhanced expression of TXNIP

Neural Wiskott-Aldrich Syndrome Protein (N-WASP) regulates actin cytoskeleton remodeling. It has been known that reduced N-WASP expression in breast and colorectal cancers is associated with poor prognosis. Here, we found reduced N-WASP expression in squamous cell carcinoma (SCC) patient samples. Th...

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Main Authors: Chung, Yat Joong, Salvi, Amrita, Kalailingam, Pazhanichamy, Alnawaz, Myra, Tan, Suat Hoon, Pan, Jiun Yit, Tan, Nguan Soon, Thanabalu, Thirumaran
Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
Format: Article
Language:English
Published: 2022
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Online Access:https://hdl.handle.net/10356/160717
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spelling sg-ntu-dr.10356-1607172023-02-28T17:12:48Z N-WASP attenuates cell proliferation and migration through ERK2-dependent enhanced expression of TXNIP Chung, Yat Joong Salvi, Amrita Kalailingam, Pazhanichamy Alnawaz, Myra Tan, Suat Hoon Pan, Jiun Yit Tan, Nguan Soon Thanabalu, Thirumaran Lee Kong Chian School of Medicine (LKCMedicine) School of Biological Sciences Science::Biological sciences Cell Adhesion Actin Cytoskeleton Neural Wiskott-Aldrich Syndrome Protein (N-WASP) regulates actin cytoskeleton remodeling. It has been known that reduced N-WASP expression in breast and colorectal cancers is associated with poor prognosis. Here, we found reduced N-WASP expression in squamous cell carcinoma (SCC) patient samples. The SCC cell line HSC-5 with reduced N-WASP expression was used to generate HSC-5CN (control) and HSC-5NW (N-WASP overexpression) cells. HSC-5NW cells had reduced cell proliferation and migration compared to HSC-5CN cells. HSC-5NW cells had increased phospho-ERK2 (extracellular signal-regulated kinase 2), phosphorylated Forkhead box protein class O1 (FOXO1) and reduced nuclear FOXO1 staining compared to HSC-5CN cells. Proteasome inhibition stabilized total FOXO1, however, not nuclear staining, suggesting that FOXO1 could be degraded in the cytoplasm. Inhibition of ERK2 enhanced nuclear FOXO1 levels and restored cell proliferation and migration of HSC-5NW to those of HSC-5CN cells, suggesting that ERK2 regulates FOXO1 activity. The expression of thioredoxin-interacting protein (TXNIP), a FOXO1 target that inhibits thioredoxin and glucose uptake, was higher in HSC-5NW cells than in HSC-5CN cells. Knockdown of TXNIP in HSC-5NW cells restored cell proliferation and migration to those of HSC-5CN cells. Thus, we propose that N-WASP regulates cell proliferation and migration via an N-WASP-ERK2-FOXO1-TXNIP pathway. Ministry of Education (MOE) Published version This work was supported by the Academic Research Fund Tier 2 (MOE 2013-T2-2-031) and Academic Research Fund Tier 1 (MOE) RG31/20 and RG154/17 grants from the Ministry of Education of Singapore. 2022-08-01T07:34:40Z 2022-08-01T07:34:40Z 2022 Journal Article Chung, Y. J., Salvi, A., Kalailingam, P., Alnawaz, M., Tan, S. H., Pan, J. Y., Tan, N. S. & Thanabalu, T. (2022). N-WASP attenuates cell proliferation and migration through ERK2-dependent enhanced expression of TXNIP. Biology, 11(4), 582-. https://dx.doi.org/10.3390/biology11040582 2079-7737 https://hdl.handle.net/10356/160717 10.3390/biology11040582 35453780 2-s2.0-85129131622 4 11 582 en MOE 2013-T2-2-031 RG31/20 RG154/17 Biology © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Biological sciences
Cell Adhesion
Actin Cytoskeleton
spellingShingle Science::Biological sciences
Cell Adhesion
Actin Cytoskeleton
Chung, Yat Joong
Salvi, Amrita
Kalailingam, Pazhanichamy
Alnawaz, Myra
Tan, Suat Hoon
Pan, Jiun Yit
Tan, Nguan Soon
Thanabalu, Thirumaran
N-WASP attenuates cell proliferation and migration through ERK2-dependent enhanced expression of TXNIP
description Neural Wiskott-Aldrich Syndrome Protein (N-WASP) regulates actin cytoskeleton remodeling. It has been known that reduced N-WASP expression in breast and colorectal cancers is associated with poor prognosis. Here, we found reduced N-WASP expression in squamous cell carcinoma (SCC) patient samples. The SCC cell line HSC-5 with reduced N-WASP expression was used to generate HSC-5CN (control) and HSC-5NW (N-WASP overexpression) cells. HSC-5NW cells had reduced cell proliferation and migration compared to HSC-5CN cells. HSC-5NW cells had increased phospho-ERK2 (extracellular signal-regulated kinase 2), phosphorylated Forkhead box protein class O1 (FOXO1) and reduced nuclear FOXO1 staining compared to HSC-5CN cells. Proteasome inhibition stabilized total FOXO1, however, not nuclear staining, suggesting that FOXO1 could be degraded in the cytoplasm. Inhibition of ERK2 enhanced nuclear FOXO1 levels and restored cell proliferation and migration of HSC-5NW to those of HSC-5CN cells, suggesting that ERK2 regulates FOXO1 activity. The expression of thioredoxin-interacting protein (TXNIP), a FOXO1 target that inhibits thioredoxin and glucose uptake, was higher in HSC-5NW cells than in HSC-5CN cells. Knockdown of TXNIP in HSC-5NW cells restored cell proliferation and migration to those of HSC-5CN cells. Thus, we propose that N-WASP regulates cell proliferation and migration via an N-WASP-ERK2-FOXO1-TXNIP pathway.
author2 Lee Kong Chian School of Medicine (LKCMedicine)
author_facet Lee Kong Chian School of Medicine (LKCMedicine)
Chung, Yat Joong
Salvi, Amrita
Kalailingam, Pazhanichamy
Alnawaz, Myra
Tan, Suat Hoon
Pan, Jiun Yit
Tan, Nguan Soon
Thanabalu, Thirumaran
format Article
author Chung, Yat Joong
Salvi, Amrita
Kalailingam, Pazhanichamy
Alnawaz, Myra
Tan, Suat Hoon
Pan, Jiun Yit
Tan, Nguan Soon
Thanabalu, Thirumaran
author_sort Chung, Yat Joong
title N-WASP attenuates cell proliferation and migration through ERK2-dependent enhanced expression of TXNIP
title_short N-WASP attenuates cell proliferation and migration through ERK2-dependent enhanced expression of TXNIP
title_full N-WASP attenuates cell proliferation and migration through ERK2-dependent enhanced expression of TXNIP
title_fullStr N-WASP attenuates cell proliferation and migration through ERK2-dependent enhanced expression of TXNIP
title_full_unstemmed N-WASP attenuates cell proliferation and migration through ERK2-dependent enhanced expression of TXNIP
title_sort n-wasp attenuates cell proliferation and migration through erk2-dependent enhanced expression of txnip
publishDate 2022
url https://hdl.handle.net/10356/160717
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