ArticleCell death & disease2018
Betulinic acid chemosensitizes breast cancer by triggering ER stress-mediated apoptosis by directly targeting GRP78.
Article in Cell death & disease, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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Who cites it
54 citing papers in PubMed, 122 citations in OpenAlex.
- RNF125 mediates the anti-breast cancer activity of betulinic acid through ubiquitin-dependent degradation of MYH9.International journal of clinical oncology · 2026Article
- Hippuric Acid Suppresses Triple-Negative Breast Cancer via the EGFL8-Notch Signaling Axis.Biomedicines · 2026Article
- The Inclusion of Dietary and Medicinal Mushrooms into Translational Oncology: Pros and Cons at the Molecular Level.International journal of molecular sciences · 2026Review
- The Biologically Active Compounds in Fruits of Cultivated Varieties and Wild Species of Apples.Molecules (Basel, Switzerland) · 2025Review
- Advances and challenges in betulinic acid therapeutics and delivery systems for breast cancer prevention and treatment.RSC advances · 2025Review
- Target discovery-directed pharmacological mechanism elucidation of bioactive natural products.Medical review (2021) · 2025Review
- The Role of Plant-Derived Natural Products as a Regulator of the Tyrosine Kinase Pathway in the Management of Lung Cancer.Current issues in molecular biology · 2025Review
- Enhanced ZBTB10 expression induced by betulinic acid inhibits gastric cancer progression by inactivating the ARRDC3/ITGB4/PI3K/AKT pathway.Cellular oncology (Dordrecht, Netherlands) · 2025Article
- Telocinobufagin suppresses malignant metastasis of undifferentiated thyroid carcinoma via modulation of the LARP1-mTOR pathway.The Kaohsiung journal of medical sciences · 2025Article
- Endoplasmic Reticulum Stress in Cancer Progression: A Comprehensive Review of Its Role and Mechanisms.International journal of medical sciences · 2025Review
- Novel glycoprotein SBSPON suppressed bladder cancer through the AKT signal pathway by inhibiting HSPA5 membrane translocation.International journal of biological sciences · 2025Article
- Complex Inhibitory Activity of Pentacyclic Triterpenoids against Cutaneous Melanoma In Vitro and In Vivo: A Literature Review and Reconstruction of Their Melanoma-Related Protein Interactome.ACS pharmacology & translational science · 2024Review
- Review on effects and mechanisms of plant-derived natural products against breast cancer bone metastasis.Heliyon · 2024Review
- Combination of betulinic acid and EGFR-TKIs exerts synergistic anti-tumor effects against wild-type EGFR NSCLC by inducing autophagy-related cell death via EGFR signaling pathway.Respiratory research · 2024Article
- Network Pharmacology and Experimental Validation to Explore the Potential Mechanism ofPharmaceuticals (Basel, Switzerland) · 2024Article
- Investigating the effect of cGRP78 vaccine against different cancer cells and its role in reducing melanoma metastasis.Research in pharmaceutical sciences · 2024Article
- The synthetic oleanane triterpenoid CDDO-2P-Im binds GRP78/BiP to induce unfolded protein response-mediated apoptosis in myeloma.Molecular oncology · 2023Article
- Target identification of small molecules: an overview of the current applications in drug discovery.BMC biotechnology · 2023Review
- Emerging roles of endoplasmic reticulum stress in the cellular plasticity of cancer cells.Frontiers in oncology · 2023Review
- Phytochemical Targeting of Mitochondria for Breast Cancer Chemoprevention, Therapy, and Sensitization.International journal of molecular sciences · 2022Review
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Stress-induced cellular defense machinery has a critical role in mediating cancer drug resistance, and targeting stress-related signaling has become a novel strategy to improve chemosensitivity. Betulinic acid (BA) is a naturally occurring pentacyclic triterpenoid with potent anticancer bioactivities in multiple malignancies, whereas its underlying mechanisms remain unclear. Here in, we found that BA has synergistic effects with taxol to induce breast cancer cells G2/M checkpoint arrest and apoptosis induction, but had little cytotoxicity effects on normal mammary epithelial cells. Drug affinity responsive target stability (DARTS) strategy further identified glucose-regulated protein 78 (GRP78) as the direct interacting target of BA. BA administration significantly elevated GRP78-mediated endoplasmic reticulum (ER) stress and resulted in the activation of protein kinase R-like ER kinase (PERK)/eukaryotic initiation factor 2a/CCAAT/enhancer-binding protein homologous protein apoptotic pathway. GRP78 silencing or ER stress inhibitor salubrinal administration was revealed to abolish the anticancer effects of BA, indicating the critical role of GRP78 in mediating the bioactivity of BA. Molecular docking and coimmunoprecipitation assay further demonstrated that BA might competitively bind with ATPase domain of GRP78 to interrupt its interaction with ER stress sensor PERK, thereby initiating the downstream apoptosis cascade. In vivo breast cancer xenografts finally validated the chemosensitizing effects of BA and its biofunction in activating GRP78 to trigger ER stress-mediated apoptosis. Taken together, our study not only uncovers GRP78 as a novel target underlying the chemosensitizing effects of BA, but also highlights GRP78-based targeting strategy as a promising approach to improve breast cancer prognosis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.