Identification of V-ATPase as a molecular sensor of SOX11-levels and potential therapeutic target for mantle cell lymphoma
Emruli, Venera Kuci LU ; Olsson, Roger LU
; Ek, Fredrik
LU
and Ek, Sara
LU
(2016)
In BMC Cancer
16(1).
- Abstract
Background: Mantle cell lymphoma (MCL) is an aggressive disease with short median survival. Molecularly, MCL is defined by the t(11;14) translocation leading to overexpression of the CCND1 gene. However, recent data show that the neural transcription factor SOX11 is a disease defining antigen and several involved signaling pathways have been pin-pointed, among others the Wnt/β-catenin pathway that is of importance for proliferation in MCL. Therefore, we evaluated a compound library focused on the Wnt pathway with the aim of identifying Wnt-related targets that regulate growth and survival in MCL, with particular focus on SOX11-dependent growth regulation. Methods: An inducible SOX11 knock-down system was used to functionally screen a... (More)
Background: Mantle cell lymphoma (MCL) is an aggressive disease with short median survival. Molecularly, MCL is defined by the t(11;14) translocation leading to overexpression of the CCND1 gene. However, recent data show that the neural transcription factor SOX11 is a disease defining antigen and several involved signaling pathways have been pin-pointed, among others the Wnt/β-catenin pathway that is of importance for proliferation in MCL. Therefore, we evaluated a compound library focused on the Wnt pathway with the aim of identifying Wnt-related targets that regulate growth and survival in MCL, with particular focus on SOX11-dependent growth regulation. Methods: An inducible SOX11 knock-down system was used to functionally screen a library of compounds (n = 75) targeting the Wnt signaling pathway. A functionally interesting target, vacuolar-type H+-ATPase (V-ATPase), was further evaluated by western blot, siRNA-mediated gene silencing, immunofluorescence, and flow cytometry. Results: We show that 15 out of 75 compounds targeting the Wnt pathway reduce proliferation in all three MCL cell lines tested. Furthermore, three substances targeting two different targets (V-ATPase and Dkk1) showed SOX11-dependent activity. Further validation analyses were focused on V-ATPase and showed that two independent V-ATPase inhibitors (bafilomycin A1 and concanamycin A) are sensitive to SOX11 levels, causing reduced anti-proliferative response in SOX11 low cells. We further show, using fluorescence imaging and flow cytometry, that V-ATPase is mainly localized to the plasma membrane in primary and MCL cell lines. Conclusions: We show that SOX11 status affect V-ATPase dependent pathways, and thus may be involved in regulating pH in intracellular and extracellular compartments. The plasma membrane localization of V-ATPase indicates that pH regulation of the immediate extracellular compartment may be of importance for receptor functionality and potentially invasiveness in vivo.
(Less)
- author
- Emruli, Venera Kuci
LU
; Olsson, Roger
LU
; Ek, Fredrik
LU
and Ek, Sara
LU
- organization
- publishing date
- 2016-07-18
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Mantle cell lymphoma, SOX11, V-ATPase
- in
- BMC Cancer
- volume
- 16
- issue
- 1
- article number
- 493
- publisher
- BioMed Central (BMC)
- external identifiers
-
- pmid:27430213
- wos:000380197700001
- scopus:84978785933
- ISSN
- 1471-2407
- DOI
- 10.1186/s12885-016-2550-4
- language
- English
- LU publication?
- yes
- id
- ac3fefb2-7a1e-4981-8869-37d115e5b18d
- date added to LUP
- 2016-08-15 16:12:47
- date last changed
- 2024-04-19 06:56:11
@article{ac3fefb2-7a1e-4981-8869-37d115e5b18d,
abstract = {{<p>Background: Mantle cell lymphoma (MCL) is an aggressive disease with short median survival. Molecularly, MCL is defined by the t(11;14) translocation leading to overexpression of the CCND1 gene. However, recent data show that the neural transcription factor SOX11 is a disease defining antigen and several involved signaling pathways have been pin-pointed, among others the Wnt/β-catenin pathway that is of importance for proliferation in MCL. Therefore, we evaluated a compound library focused on the Wnt pathway with the aim of identifying Wnt-related targets that regulate growth and survival in MCL, with particular focus on SOX11-dependent growth regulation. Methods: An inducible SOX11 knock-down system was used to functionally screen a library of compounds (n = 75) targeting the Wnt signaling pathway. A functionally interesting target, vacuolar-type H<sup>+</sup>-ATPase (V-ATPase), was further evaluated by western blot, siRNA-mediated gene silencing, immunofluorescence, and flow cytometry. Results: We show that 15 out of 75 compounds targeting the Wnt pathway reduce proliferation in all three MCL cell lines tested. Furthermore, three substances targeting two different targets (V-ATPase and Dkk1) showed SOX11-dependent activity. Further validation analyses were focused on V-ATPase and showed that two independent V-ATPase inhibitors (bafilomycin A1 and concanamycin A) are sensitive to SOX11 levels, causing reduced anti-proliferative response in SOX11 low cells. We further show, using fluorescence imaging and flow cytometry, that V-ATPase is mainly localized to the plasma membrane in primary and MCL cell lines. Conclusions: We show that SOX11 status affect V-ATPase dependent pathways, and thus may be involved in regulating pH in intracellular and extracellular compartments. The plasma membrane localization of V-ATPase indicates that pH regulation of the immediate extracellular compartment may be of importance for receptor functionality and potentially invasiveness in vivo.</p>}},
author = {{Emruli, Venera Kuci and Olsson, Roger and Ek, Fredrik and Ek, Sara}},
issn = {{1471-2407}},
keywords = {{Mantle cell lymphoma; SOX11; V-ATPase}},
language = {{eng}},
month = {{07}},
number = {{1}},
publisher = {{BioMed Central (BMC)}},
series = {{BMC Cancer}},
title = {{Identification of V-ATPase as a molecular sensor of SOX11-levels and potential therapeutic target for mantle cell lymphoma}},
url = {{http://dx.doi.org/10.1186/s12885-016-2550-4}},
doi = {{10.1186/s12885-016-2550-4}},
volume = {{16}},
year = {{2016}},
}