Cargando…
Betulinic Acid-Mediated Tuning of PERK/CHOP Signaling by Sp1 Inhibition as a Novel Therapeutic Strategy for Glioblastoma
Patients with glioblastoma are at high risk of local recurrences after initial treatment with standard therapy, and recurrent tumor cells appear to be resistant to first-line drug temozolomide. Thus, finding an effective second-line agent for treating primary and recurrent glioblastomas is critical....
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226172/ https://www.ncbi.nlm.nih.gov/pubmed/32326583 http://dx.doi.org/10.3390/cancers12040981 |
_version_ | 1783534228405747712 |
---|---|
author | Lo, Wei-Lun Hsu, Tsung-I Yang, Wen-Bin Kao, Tzu-Jen Wu, Ming-Hsiao Huang, Yung-Ning Yeh, Shiu-Hwa Chuang, Jian-Ying |
author_facet | Lo, Wei-Lun Hsu, Tsung-I Yang, Wen-Bin Kao, Tzu-Jen Wu, Ming-Hsiao Huang, Yung-Ning Yeh, Shiu-Hwa Chuang, Jian-Ying |
author_sort | Lo, Wei-Lun |
collection | PubMed |
description | Patients with glioblastoma are at high risk of local recurrences after initial treatment with standard therapy, and recurrent tumor cells appear to be resistant to first-line drug temozolomide. Thus, finding an effective second-line agent for treating primary and recurrent glioblastomas is critical. Betulinic acid (BA), a natural product of plant origin, can cross the blood–brain barrier. Here, we investigated the antitumor effects of BA on typical glioblastoma cell lines and primary glioblastoma cells from patients, as well as corresponding temozolomide-resistant cells. Our findings verified that BA significantly reduced growth in all examined cells. Furthermore, gene-expression array analysis showed that the unfolded-protein response was significantly affected by BA. Moreover, BA treatment increased activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK)/C/EBP homologous protein (CHOP) apoptotic pathway, and reduced specificity protein 1 (Sp1) expression. However, Sp1 overexpression reversed the observed cell-growth inhibition and PERK/CHOP signaling activation induced by BA. Because temozolomide-resistant cells exhibited significantly increased Sp1 expression, we concluded that Sp1-mediated PERK/CHOP signaling inhibition protects glioblastoma against cancer therapies; hence, BA treatment targeting this pathway can be considered as an effective therapeutic strategy to overcome such chemoresistance and tumor relapse. |
format | Online Article Text |
id | pubmed-7226172 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-72261722020-05-18 Betulinic Acid-Mediated Tuning of PERK/CHOP Signaling by Sp1 Inhibition as a Novel Therapeutic Strategy for Glioblastoma Lo, Wei-Lun Hsu, Tsung-I Yang, Wen-Bin Kao, Tzu-Jen Wu, Ming-Hsiao Huang, Yung-Ning Yeh, Shiu-Hwa Chuang, Jian-Ying Cancers (Basel) Article Patients with glioblastoma are at high risk of local recurrences after initial treatment with standard therapy, and recurrent tumor cells appear to be resistant to first-line drug temozolomide. Thus, finding an effective second-line agent for treating primary and recurrent glioblastomas is critical. Betulinic acid (BA), a natural product of plant origin, can cross the blood–brain barrier. Here, we investigated the antitumor effects of BA on typical glioblastoma cell lines and primary glioblastoma cells from patients, as well as corresponding temozolomide-resistant cells. Our findings verified that BA significantly reduced growth in all examined cells. Furthermore, gene-expression array analysis showed that the unfolded-protein response was significantly affected by BA. Moreover, BA treatment increased activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK)/C/EBP homologous protein (CHOP) apoptotic pathway, and reduced specificity protein 1 (Sp1) expression. However, Sp1 overexpression reversed the observed cell-growth inhibition and PERK/CHOP signaling activation induced by BA. Because temozolomide-resistant cells exhibited significantly increased Sp1 expression, we concluded that Sp1-mediated PERK/CHOP signaling inhibition protects glioblastoma against cancer therapies; hence, BA treatment targeting this pathway can be considered as an effective therapeutic strategy to overcome such chemoresistance and tumor relapse. MDPI 2020-04-15 /pmc/articles/PMC7226172/ /pubmed/32326583 http://dx.doi.org/10.3390/cancers12040981 Text en © 2020 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 (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Lo, Wei-Lun Hsu, Tsung-I Yang, Wen-Bin Kao, Tzu-Jen Wu, Ming-Hsiao Huang, Yung-Ning Yeh, Shiu-Hwa Chuang, Jian-Ying Betulinic Acid-Mediated Tuning of PERK/CHOP Signaling by Sp1 Inhibition as a Novel Therapeutic Strategy for Glioblastoma |
title | Betulinic Acid-Mediated Tuning of PERK/CHOP Signaling by Sp1 Inhibition as a Novel Therapeutic Strategy for Glioblastoma |
title_full | Betulinic Acid-Mediated Tuning of PERK/CHOP Signaling by Sp1 Inhibition as a Novel Therapeutic Strategy for Glioblastoma |
title_fullStr | Betulinic Acid-Mediated Tuning of PERK/CHOP Signaling by Sp1 Inhibition as a Novel Therapeutic Strategy for Glioblastoma |
title_full_unstemmed | Betulinic Acid-Mediated Tuning of PERK/CHOP Signaling by Sp1 Inhibition as a Novel Therapeutic Strategy for Glioblastoma |
title_short | Betulinic Acid-Mediated Tuning of PERK/CHOP Signaling by Sp1 Inhibition as a Novel Therapeutic Strategy for Glioblastoma |
title_sort | betulinic acid-mediated tuning of perk/chop signaling by sp1 inhibition as a novel therapeutic strategy for glioblastoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226172/ https://www.ncbi.nlm.nih.gov/pubmed/32326583 http://dx.doi.org/10.3390/cancers12040981 |
work_keys_str_mv | AT loweilun betulinicacidmediatedtuningofperkchopsignalingbysp1inhibitionasanoveltherapeuticstrategyforglioblastoma AT hsutsungi betulinicacidmediatedtuningofperkchopsignalingbysp1inhibitionasanoveltherapeuticstrategyforglioblastoma AT yangwenbin betulinicacidmediatedtuningofperkchopsignalingbysp1inhibitionasanoveltherapeuticstrategyforglioblastoma AT kaotzujen betulinicacidmediatedtuningofperkchopsignalingbysp1inhibitionasanoveltherapeuticstrategyforglioblastoma AT wuminghsiao betulinicacidmediatedtuningofperkchopsignalingbysp1inhibitionasanoveltherapeuticstrategyforglioblastoma AT huangyungning betulinicacidmediatedtuningofperkchopsignalingbysp1inhibitionasanoveltherapeuticstrategyforglioblastoma AT yehshiuhwa betulinicacidmediatedtuningofperkchopsignalingbysp1inhibitionasanoveltherapeuticstrategyforglioblastoma AT chuangjianying betulinicacidmediatedtuningofperkchopsignalingbysp1inhibitionasanoveltherapeuticstrategyforglioblastoma |