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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....

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Autores principales: Lo, Wei-Lun, Hsu, Tsung-I, Yang, Wen-Bin, Kao, Tzu-Jen, Wu, Ming-Hsiao, Huang, Yung-Ning, Yeh, Shiu-Hwa, Chuang, Jian-Ying
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
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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.
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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
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