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Betulinic Acid-Mediated Tuning of PERK/CHOP Signaling by Sp1 Inhibition as a Novel Therapeutic Strategy for Glioblastoma.

ABSTRACT: 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.

SUBMITTER: Lo WL

PROVIDER: S-EPMC7226172 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Betulinic Acid-Mediated Tuning of PERK/CHOP Signaling by Sp1 Inhibition as a Novel Therapeutic Strategy for Glioblastoma.

Lo Wei-Lun WL Hsu Tsung-I TI Yang Wen-Bin WB Kao Tzu-Jen TJ Wu Ming-Hsiao MH Huang Yung-Ning YN Yeh Shiu-Hwa SH Chuang Jian-Ying JY

Cancers 20200415 4

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 glioblastom ...[more]

PMID: 32326583

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Project description:Objective In periodontitis, excessive oxidative stress combined with subsequent apoptosis and cell death further exacerbated periodontium destruction. TRPA1, an important transient receptor potential (TRP) cation channel, may participate in the process. This study is aimed at exploring the role and the novel therapeutic function of TRPA1 in periodontitis. Methods Periodontal ligament cells or tissues derived from healthy and periodontitis (PDLCs/Ts and P-PDLCs/Ts) were used to analyze the oxidative and apoptotic levels and TRPA1 expression. TRPA1 inhibitor (HC030031) was administrated in inflammation induced by P. gingivalis lipopolysaccharide (P.g.LPS) to investigate the oxidative and apoptotic levels of PDLCs. The morphology of the endoplasmic reticulum (ER) and mitochondria was identified by transmission electron microscope, and the PERK/eIF2α/ATF-4/CHOP signal pathways were detected. Finally, HC030031 was administered to periodontitis mice to evaluate its effect on apoptotic and oxidative levels in the periodontium and the relieving of periodontitis. Results The oxidative, apoptotic levels and TRPA1 expression were higher in P-PDLC/Ts from periodontitis patients and in P.g.LPS-induced inflammatory PDLCs. TRPA1 inhibitor significantly decreased the intracellular calcium, oxidative stress, and apoptosis of inflammatory PDLCs and decreased ER stress by downregulating PERK/eIF2α/ATF-4/CHOP pathways. Meanwhile, the overall calcium ion decrease induced by EGTA also exerted similar antiapoptosis and antioxidative stress functions. In vivo, HC030031 significantly reduced oxidative stress and apoptosis in the gingiva and periodontal ligament, and less periodontium destruction was observed. Conclusion TRPA1 was highly related to periodontitis, and TRPA1 inhibitor significantly reduced oxidative and apoptotic levels in inflammatory PDLCs via inhibiting ER stress by downregulating PERK/eIF2α/ATF-4/CHOP pathways. It also reduced the oxidative stress and apoptosis in periodontitis mice thus ameliorating the development of periodontitis.

Dataset Information

Betulinic Acid-Mediated Tuning of PERK/CHOP Signaling by Sp1 Inhibition as a Novel Therapeutic Strategy for Glioblastoma.

Publications

Betulinic Acid-Mediated Tuning of PERK/CHOP Signaling by Sp1 Inhibition as a Novel Therapeutic Strategy for Glioblastoma.

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