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Atranorin Impedes Glioma Invasiveness and Progression by Inhibiting the Epithelial-Mesenchymal Transition and Stemness in Monotherapy and in Combination Therapy With Temozolomide

Zhou, Rui ; Ahn, Eun-Jung ; Bhosle, Suresh R ; Yu, Ju Yeon ; Yang, Yi ; Park, So-Yeon ; Taş, İsa LU orcid ; Gamage, Chathurika ; Pulat, Sultan and Varlı, Mücahit , et al. (2026) In Phytotherapy Research 40(1). p.159-175
Abstract

Lichens are commensal organisms that contain secondary metabolites such as atranorin, which have intrinsic bioactive properties, including anticancer effects. The present study aimed to investigate the therapeutic potential and molecular mechanisms of atranorin and its hydrolytic derivatives in monotherapy and in combination treatment with temozolomide in glioma. The effects of atranorin on gliomas were investigated using an MTT assay, transwell invasion assay, spheroid formation assay, clonogenic assay, reporter assay, western blotting, quantitative real-time PCR, an orthotopic mouse glioma model with in vivo bioluminescence imaging, and immunohistochemical staining. Here, we found that atranorin inhibited glioma cell invasion and... (More)

Lichens are commensal organisms that contain secondary metabolites such as atranorin, which have intrinsic bioactive properties, including anticancer effects. The present study aimed to investigate the therapeutic potential and molecular mechanisms of atranorin and its hydrolytic derivatives in monotherapy and in combination treatment with temozolomide in glioma. The effects of atranorin on gliomas were investigated using an MTT assay, transwell invasion assay, spheroid formation assay, clonogenic assay, reporter assay, western blotting, quantitative real-time PCR, an orthotopic mouse glioma model with in vivo bioluminescence imaging, and immunohistochemical staining. Here, we found that atranorin inhibited glioma cell invasion and spheroid formation by downregulating epithelial-mesenchymal transition (EMT) and cancer stemness regulators and markers. The atranorin hydrolytic derivatives atraric acid and haematommic acid inhibited glioma cell invasiveness and stemness, respectively. Also, major oncogenic signaling pathways-Wnt, AP-1, STAT, Hedgehog, Notch, and NF-κB-were investigated, revealing that atranorin robustly decreased the transcriptional activities of TOPFLASH, AP-1, Gli, CBF1/Su(H)/Lag-1, hairy/enhancer of Split, and expression of the related downstream targets such as β-catenin, cyclin-D1, c-myc, c-Jun, c-Fos, Gli1, Gli2, Smoothened, and Notch 1 intracellular domain. Moreover, atranorin-mediated upregulation of Dusp3 and Ptpn1 suppressed the invasiveness and stemness of gliomas by dephosphorylating STAT and NF-κB. Importantly, atranorin exerts synergistic antiglioma effects on invasion and spheroid formation in combination treatment with temozolomide. These findings identified that atranorin could be developed as a specific therapy to target EMT and CSC pathways to suppress malignant behaviors in glioma.

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publishing date
type
Contribution to journal
publication status
published
subject
keywords
Temozolomide/pharmacology, Epithelial-Mesenchymal Transition/drug effects, Glioma/drug therapy, Animals, Humans, Cell Line, Tumor, Mice, Neoplastic Stem Cells/drug effects, Neoplasm Invasiveness, Signal Transduction/drug effects, Mice, Nude, Brain Neoplasms/drug therapy
in
Phytotherapy Research
volume
40
issue
1
pages
159 - 175
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:105021834872
  • pmid:41239946
ISSN
1099-1573
DOI
10.1002/ptr.70126
language
English
LU publication?
no
additional info
© 2025 John Wiley & Sons Ltd.
id
137310c2-2cd3-4655-b98a-31dad065431e
date added to LUP
2026-09-23 15:54:49
date last changed
2026-09-24 04:01:32
@article{137310c2-2cd3-4655-b98a-31dad065431e,
  abstract     = {{<p>Lichens are commensal organisms that contain secondary metabolites such as atranorin, which have intrinsic bioactive properties, including anticancer effects. The present study aimed to investigate the therapeutic potential and molecular mechanisms of atranorin and its hydrolytic derivatives in monotherapy and in combination treatment with temozolomide in glioma. The effects of atranorin on gliomas were investigated using an MTT assay, transwell invasion assay, spheroid formation assay, clonogenic assay, reporter assay, western blotting, quantitative real-time PCR, an orthotopic mouse glioma model with in vivo bioluminescence imaging, and immunohistochemical staining. Here, we found that atranorin inhibited glioma cell invasion and spheroid formation by downregulating epithelial-mesenchymal transition (EMT) and cancer stemness regulators and markers. The atranorin hydrolytic derivatives atraric acid and haematommic acid inhibited glioma cell invasiveness and stemness, respectively. Also, major oncogenic signaling pathways-Wnt, AP-1, STAT, Hedgehog, Notch, and NF-κB-were investigated, revealing that atranorin robustly decreased the transcriptional activities of TOPFLASH, AP-1, Gli, CBF1/Su(H)/Lag-1, hairy/enhancer of Split, and expression of the related downstream targets such as β-catenin, cyclin-D1, c-myc, c-Jun, c-Fos, Gli1, Gli2, Smoothened, and Notch 1 intracellular domain. Moreover, atranorin-mediated upregulation of Dusp3 and Ptpn1 suppressed the invasiveness and stemness of gliomas by dephosphorylating STAT and NF-κB. Importantly, atranorin exerts synergistic antiglioma effects on invasion and spheroid formation in combination treatment with temozolomide. These findings identified that atranorin could be developed as a specific therapy to target EMT and CSC pathways to suppress malignant behaviors in glioma.</p>}},
  author       = {{Zhou, Rui and Ahn, Eun-Jung and Bhosle, Suresh R and Yu, Ju Yeon and Yang, Yi and Park, So-Yeon and Taş, İsa and Gamage, Chathurika and Pulat, Sultan and Varlı, Mücahit and Hur, Jae-Seoun and Kim, Kyung Keun and Lee, Kyung-Hwa and Ha, Hyung-Ho and Kim, Sang Kyum and Moon, Kyung-Sub and Kim, Hangun}},
  issn         = {{1099-1573}},
  keywords     = {{Temozolomide/pharmacology; Epithelial-Mesenchymal Transition/drug effects; Glioma/drug therapy; Animals; Humans; Cell Line, Tumor; Mice; Neoplastic Stem Cells/drug effects; Neoplasm Invasiveness; Signal Transduction/drug effects; Mice, Nude; Brain Neoplasms/drug therapy}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{159--175}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Phytotherapy Research}},
  title        = {{Atranorin Impedes Glioma Invasiveness and Progression by Inhibiting the Epithelial-Mesenchymal Transition and Stemness in Monotherapy and in Combination Therapy With Temozolomide}},
  url          = {{http://dx.doi.org/10.1002/ptr.70126}},
  doi          = {{10.1002/ptr.70126}},
  volume       = {{40}},
  year         = {{2026}},
}