ArticleCell death & disease2014
HKH40A downregulates GRP78/BiP expression in cancer cells.
Article in Cell death & disease, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 46 citations in OpenAlex.
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- Mechanical effect of protein glycosylation on BiP-mediated post-translational translocation and folding in the endoplasmic reticulum.Biophysical reviews · 2025Review
- Review
- Diastereomers of Coibamide A Show Altered Sec61 Client Selectivity and Ligand-Dependent Activity against Patient-Derived Glioma Stem-like Cells.ACS pharmacology & translational science · 2024Article
- Anti-cancer potential of zerumbone in cancer and glioma: current trends and future perspectives.Medical oncology (Northwood, London, England) · 2024Review
- Effect of temperature and nucleotide on the binding of BiP chaperone to a protein substrate.Protein science : a publication of the Protein Society · 2023Article
- The emerging role of pyroptosis in pediatric cancers: from mechanism to therapy.Journal of hematology & oncology · 2022Review
- Chemogenomic and bioinformatic profiling of ERdj paralogs underpins their unique roles in cancer.Cell stress & chaperones · 2021Article
- Preliminary Virtual Screening Studies to Identify GRP78 Inhibitors Which May Interfere with SARS-CoV-2 Infection.Pharmaceuticals (Basel, Switzerland) · 2020Article
- Dual role of Endoplasmic Reticulum Stress-Mediated Unfolded Protein Response Signaling Pathway in Carcinogenesis.International journal of molecular sciences · 2019Review
- Inhibition of the hexosamine biosynthesis pathway potentiates cisplatin cytotoxicity by decreasing BiP expression in non-small-cell lung cancer cells.Molecular carcinogenesis · 2019Article
- Salvianolic acid A inhibits tumor-associated angiogenesis by blocking GRP78 secretion.Naunyn-Schmiedeberg's archives of pharmacology · 2019Article
- Chemotherapy Resistance Explained through Endoplasmic Reticulum Stress-Dependent Signaling.Cancers · 2019Review
- Virus and tumor microenvironment induced ER stress and unfolded protein response: from complexity to therapeutics.Oncotarget · 2018Review
- Heme Induces Endoplasmic Reticulum Stress (HIER Stress) in Human Aortic Smooth Muscle Cells.Frontiers in physiology · 2018Article
- PERK-opathies: An Endoplasmic Reticulum Stress Mechanism Underlying Neurodegeneration.Current Alzheimer research · 2016Review
- Interplay between unfolded protein response and autophagy promotes tumor drug resistance.Oncology letters · 2015Article
- Endoplasmic reticulum stress, genome damage, and cancer.Frontiers in oncology · 2015Review
- Mechanisms of Translocation of ER Chaperones to the Cell Surface and Immunomodulatory Roles in Cancer and Autoimmunity.Frontiers in oncology · 2015Review
- Secretory prostate apoptosis response (Par)-4 sensitizes multicellular spheroids (MCS) of glioblastoma multiforme cells to tamoxifen-induced cell death.FEBS open bio · 2015Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
HKH40A, the 8-methoxy analog of WMC79, is a synthetic agent with promising in vitro and in vivo antitumor activity, especially against solid tumors. However, molecular mechanisms underlying its antitumor effects are poorly understood. Here, we report that HKH40A markedly reduces the level of GRP78/BiP protein in cancer cell lines of various origin. In this study, we show that HKH40A not only downregulates transcription of GRP78 but also directly binds to the isolated protein and induces its proteosomal degradation. Knockdown of BiP increased the efficacy of the drug and overexpression of BiP diminished its activity. BiP is generally highly elevated in solid tumors having a pivotal role in cancer cell survival and chemoresistance, and has been suggested as a novel target for therapeutic intervention. We show that reduction of BiP level by HKH40A impairs its function and induces unfolded protein response as evidenced by the activation of IRE1α, ATF6 and PERK. This leads to a series of downstream events, including sustained eIF2α phosphorylation, increased abundance of spliced XBP1 mRNA and protein levels of ATF4 and CHOP. We also demonstrate that HKH40A inhibited tumor formation in an in vivo xenograft tumor model. Collectively, our data show that HKH40A reduces BiP levels and this could have an important role in the activity of HKH40A against cancer cells.
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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.