Cargando…

The JNK signaling pathway plays a key role in methuosis (non-apoptotic cell death) induced by MOMIPP in glioblastoma

BACKGROUND: Synthetic indolyl- pyridinyl- propenones (IPPs) induce methuosis, a form of non-apoptotic cell death, in glioblastoma and other cancer cell lines. Methuosis is characterized by accumulation of cytoplasmic vacuoles derived from macropinosomes and late endosomes, followed by metabolic fail...

Descripción completa

Detalles Bibliográficos
Autores principales: Li, Zehui, Mbah, Nneka E., Overmeyer, Jean H., Sarver, Jeffrey G., George, Sage, Trabbic, Christopher J., Erhardt, Paul W., Maltese, William A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335761/
https://www.ncbi.nlm.nih.gov/pubmed/30651087
http://dx.doi.org/10.1186/s12885-019-5288-y
_version_ 1783387951647948800
author Li, Zehui
Mbah, Nneka E.
Overmeyer, Jean H.
Sarver, Jeffrey G.
George, Sage
Trabbic, Christopher J.
Erhardt, Paul W.
Maltese, William A.
author_facet Li, Zehui
Mbah, Nneka E.
Overmeyer, Jean H.
Sarver, Jeffrey G.
George, Sage
Trabbic, Christopher J.
Erhardt, Paul W.
Maltese, William A.
author_sort Li, Zehui
collection PubMed
description BACKGROUND: Synthetic indolyl- pyridinyl- propenones (IPPs) induce methuosis, a form of non-apoptotic cell death, in glioblastoma and other cancer cell lines. Methuosis is characterized by accumulation of cytoplasmic vacuoles derived from macropinosomes and late endosomes, followed by metabolic failure and rupture of the plasma membrane. However, not all IPPs that cause vacuolization are cytotoxic. The main goals of the present study were to identify key signaling pathways that contribute to methuosis induced by cytotoxic IPPs and to evaluate the anti-tumor potential of a prototype IPP in vivo. METHODS: We utilized metabolic flux analysis, glucose uptake, immunoblotting, and selective pharmacological inhibitors to compare the effects of closely related cytotoxic and non-cytotoxic IPPs in cultured glioblastoma cells. To determine whether the use of methuosis-inducing IPPs might be feasible in a therapeutic context, we quantified the distribution of our lead IPP compound, MOMIPP, in mouse plasma and brain, and tested its ability to inhibit tumor growth in an intracerebral glioblastoma xenograft model. RESULTS: The cytotoxic IPP compound, MOMIPP, causes early disruptions of glucose uptake and glycolytic metabolism. Coincident with these metabolic changes, MOMIPP selectively activates the JNK1/2 stress kinase pathway, resulting in phosphorylation of c-Jun, Bcl-2 and Bcl-xL. At the same concentration, the non-cytotoxic analog, MOPIPP, does not activate these pathways. Pharmacologic inhibition of JNK activity promotes survival, even when cells are extensively vacuolated, but suppression of c-Jun transcriptional activity offers no protection. MOMIPP readily penetrates the blood-brain barrier and is moderately effective in suppressing progression of intracerebral glioblastoma xenografts. CONCLUSIONS: The results suggest that interference with glucose uptake and induction of JNK-mediated phosphorylation of pro-survival members of the Bcl-2 family represent key events in the methuosis death process. In addition to providing new insights into the underlying molecular mechanism of methuosis, the results indicate that compounds of the cytotoxic IPP class may have potential for further development as therapeutic agents for brain tumors. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12885-019-5288-y) contains supplementary material, which is available to authorized users.
format Online
Article
Text
id pubmed-6335761
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-63357612019-01-23 The JNK signaling pathway plays a key role in methuosis (non-apoptotic cell death) induced by MOMIPP in glioblastoma Li, Zehui Mbah, Nneka E. Overmeyer, Jean H. Sarver, Jeffrey G. George, Sage Trabbic, Christopher J. Erhardt, Paul W. Maltese, William A. BMC Cancer Research Article BACKGROUND: Synthetic indolyl- pyridinyl- propenones (IPPs) induce methuosis, a form of non-apoptotic cell death, in glioblastoma and other cancer cell lines. Methuosis is characterized by accumulation of cytoplasmic vacuoles derived from macropinosomes and late endosomes, followed by metabolic failure and rupture of the plasma membrane. However, not all IPPs that cause vacuolization are cytotoxic. The main goals of the present study were to identify key signaling pathways that contribute to methuosis induced by cytotoxic IPPs and to evaluate the anti-tumor potential of a prototype IPP in vivo. METHODS: We utilized metabolic flux analysis, glucose uptake, immunoblotting, and selective pharmacological inhibitors to compare the effects of closely related cytotoxic and non-cytotoxic IPPs in cultured glioblastoma cells. To determine whether the use of methuosis-inducing IPPs might be feasible in a therapeutic context, we quantified the distribution of our lead IPP compound, MOMIPP, in mouse plasma and brain, and tested its ability to inhibit tumor growth in an intracerebral glioblastoma xenograft model. RESULTS: The cytotoxic IPP compound, MOMIPP, causes early disruptions of glucose uptake and glycolytic metabolism. Coincident with these metabolic changes, MOMIPP selectively activates the JNK1/2 stress kinase pathway, resulting in phosphorylation of c-Jun, Bcl-2 and Bcl-xL. At the same concentration, the non-cytotoxic analog, MOPIPP, does not activate these pathways. Pharmacologic inhibition of JNK activity promotes survival, even when cells are extensively vacuolated, but suppression of c-Jun transcriptional activity offers no protection. MOMIPP readily penetrates the blood-brain barrier and is moderately effective in suppressing progression of intracerebral glioblastoma xenografts. CONCLUSIONS: The results suggest that interference with glucose uptake and induction of JNK-mediated phosphorylation of pro-survival members of the Bcl-2 family represent key events in the methuosis death process. In addition to providing new insights into the underlying molecular mechanism of methuosis, the results indicate that compounds of the cytotoxic IPP class may have potential for further development as therapeutic agents for brain tumors. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12885-019-5288-y) contains supplementary material, which is available to authorized users. BioMed Central 2019-01-16 /pmc/articles/PMC6335761/ /pubmed/30651087 http://dx.doi.org/10.1186/s12885-019-5288-y Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Li, Zehui
Mbah, Nneka E.
Overmeyer, Jean H.
Sarver, Jeffrey G.
George, Sage
Trabbic, Christopher J.
Erhardt, Paul W.
Maltese, William A.
The JNK signaling pathway plays a key role in methuosis (non-apoptotic cell death) induced by MOMIPP in glioblastoma
title The JNK signaling pathway plays a key role in methuosis (non-apoptotic cell death) induced by MOMIPP in glioblastoma
title_full The JNK signaling pathway plays a key role in methuosis (non-apoptotic cell death) induced by MOMIPP in glioblastoma
title_fullStr The JNK signaling pathway plays a key role in methuosis (non-apoptotic cell death) induced by MOMIPP in glioblastoma
title_full_unstemmed The JNK signaling pathway plays a key role in methuosis (non-apoptotic cell death) induced by MOMIPP in glioblastoma
title_short The JNK signaling pathway plays a key role in methuosis (non-apoptotic cell death) induced by MOMIPP in glioblastoma
title_sort jnk signaling pathway plays a key role in methuosis (non-apoptotic cell death) induced by momipp in glioblastoma
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335761/
https://www.ncbi.nlm.nih.gov/pubmed/30651087
http://dx.doi.org/10.1186/s12885-019-5288-y
work_keys_str_mv AT lizehui thejnksignalingpathwayplaysakeyroleinmethuosisnonapoptoticcelldeathinducedbymomippinglioblastoma
AT mbahnnekae thejnksignalingpathwayplaysakeyroleinmethuosisnonapoptoticcelldeathinducedbymomippinglioblastoma
AT overmeyerjeanh thejnksignalingpathwayplaysakeyroleinmethuosisnonapoptoticcelldeathinducedbymomippinglioblastoma
AT sarverjeffreyg thejnksignalingpathwayplaysakeyroleinmethuosisnonapoptoticcelldeathinducedbymomippinglioblastoma
AT georgesage thejnksignalingpathwayplaysakeyroleinmethuosisnonapoptoticcelldeathinducedbymomippinglioblastoma
AT trabbicchristopherj thejnksignalingpathwayplaysakeyroleinmethuosisnonapoptoticcelldeathinducedbymomippinglioblastoma
AT erhardtpaulw thejnksignalingpathwayplaysakeyroleinmethuosisnonapoptoticcelldeathinducedbymomippinglioblastoma
AT maltesewilliama thejnksignalingpathwayplaysakeyroleinmethuosisnonapoptoticcelldeathinducedbymomippinglioblastoma
AT lizehui jnksignalingpathwayplaysakeyroleinmethuosisnonapoptoticcelldeathinducedbymomippinglioblastoma
AT mbahnnekae jnksignalingpathwayplaysakeyroleinmethuosisnonapoptoticcelldeathinducedbymomippinglioblastoma
AT overmeyerjeanh jnksignalingpathwayplaysakeyroleinmethuosisnonapoptoticcelldeathinducedbymomippinglioblastoma
AT sarverjeffreyg jnksignalingpathwayplaysakeyroleinmethuosisnonapoptoticcelldeathinducedbymomippinglioblastoma
AT georgesage jnksignalingpathwayplaysakeyroleinmethuosisnonapoptoticcelldeathinducedbymomippinglioblastoma
AT trabbicchristopherj jnksignalingpathwayplaysakeyroleinmethuosisnonapoptoticcelldeathinducedbymomippinglioblastoma
AT erhardtpaulw jnksignalingpathwayplaysakeyroleinmethuosisnonapoptoticcelldeathinducedbymomippinglioblastoma
AT maltesewilliama jnksignalingpathwayplaysakeyroleinmethuosisnonapoptoticcelldeathinducedbymomippinglioblastoma