Suppression of head and neck cancer cell survival and cisplatin resistance by GRP78 small molecule inhibitor YUM70

Yamamoto, Vicky; Wang, Bintao; Lee, Amy

doi:10.3389/fonc.2022.1044699

Cited by 6 publications

(8 citation statements)

References 44 publications

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“…GRP78 can translocate to the nucleus and regulate transcription of the epidermal growth factor receptor (EGFR) [28]. As would be expected as a regulator of EGFR, RAS, and PI3K signaling, knock down or small molecule inhibition of GRP78 enhances tumor cell chemosensitivity [29][30][31][32]. Equally, over-expression of GRP78 stabilizes protein expression, suppresses ER stress signaling and maintains tumor cell viability.…”

Section: Discussionmentioning

confidence: 99%

Phase 2 Study of Sorafenib, Valproic Acid, and Sildenafil in the Treatment of Recurrent High-Grade Glioma

Poklepovic,

Shah,

Tombes

et al. 2024

Preprint

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Here we report a single-center phase 2 clinical trial combining sorafenib tosylate, valproic acid, and sildenafil for the treatment of patients with recurrent high-grade glioma (NCT01817751). Clinical toxicities were Grade 1 and Grade 2, with one Grade 3 toxicity for maculopapular rash (6.4%). For all evaluable patients the median progression free survival (PFS) was 3.65 months and overall survival (OS) 10.0 months. There was promising evidence showing clinical activity and benefit. In the 33 evaluable patients, low protein levels of the chaperone GRP78 (HSPA5) was significantly associated with a better OS (p < 0.0026). A correlation between the expression of PDGFR; and OS approached significance (p < 0.0728). Five patients presently have a mean OS of 73.6 months and remain alive. This is the first therapeutic intervention glioblastoma trial to significantly associate GRP78α expression to overall survival. Our data argue that the combination of sorafenib tosylate, valproic acid, and sildenafil requires additional clinical development in the recurrent glioma population.

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Section: Discussionmentioning

confidence: 99%

Phase 2 Study of Sorafenib, Valproic Acid, and Sildenafil in the Treatment of Recurrent High-Grade Glioma

Poklepovic,

Shah,

Tombes

et al. 2024

Preprint

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“…Overall, our study suggests that the inhibition of GRP78, in general, may be a promising approach to combat SARS-CoV-2 infection. A wide range of GRP78 inhibitors have been reported, including natural products, synthetic molecules, specific peptides, and monoclonal antibodies [ 4 , 7 , 21 , 25 , 34 , 35 , 36 , 37 ]. Our study supports the further investigation of GRP78 inhibition as a viable approach with which to treat COVID-19 and the development of GRP78 inhibitors for the treatment of viral infections and other diseases that depend on GRP78.…”

Section: Discussionmentioning

confidence: 99%

GRP78 Inhibitor YUM70 Suppresses SARS-CoV-2 Viral Entry, Spike Protein Production and Ameliorates Lung Damage

Shin

Hernandéz

et al. 2023

Viruses

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 pandemic, has given rise to many new variants with increased transmissibility and the ability to evade vaccine protection. The 78-kDa glucose-regulated protein (GRP78) is a major endoplasmic reticulum (ER) chaperone that has been recently implicated as an essential host factor for SARS-CoV-2 entry and infection. In this study, we investigated the efficacy of YUM70, a small molecule inhibitor of GRP78, to block SARS-CoV-2 viral entry and infection in vitro and in vivo. Using human lung epithelial cells and pseudoviral particles carrying spike proteins from different SARS-CoV-2 variants, we found that YUM70 was equally effective at blocking viral entry mediated by original and variant spike proteins. Furthermore, YUM70 reduced SARS-CoV-2 infection without impacting cell viability in vitro and suppressed viral protein production following SARS-CoV-2 infection. Additionally, YUM70 rescued the cell viability of multi-cellular human lung and liver 3D organoids transfected with a SARS-CoV-2 replicon. Importantly, YUM70 treatment ameliorated lung damage in transgenic mice infected with SARS-CoV-2, which correlated with reduced weight loss and longer survival. Thus, GRP78 inhibition may be a promising approach to augment existing therapies to block SARS-CoV-2, its variants, and other viruses that utilize GRP78 for entry and infection.

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“…In HNSCC, cisplatin [ cis -diamminedichloroplatinum(II) (CDDP)] is a commonly used chemotherapy that halts proliferation by inducing both cell cycle arrest and cell death. However, cisplatin resistance is a major cause of tumor relapse and patients’ death ( 23 ). The complexity of cisplatin resistance in HNSCC involves the occurrence of cancer stem cells, autophagy, epithelial–mesenchymal transition, drug efflux, and metabolic reprogramming ( 24 ).…”

Section: Introductionmentioning

confidence: 99%

The two-faced role of RNA methyltransferase METTL3 on cellular response to cisplatin in head and neck squamous cell carcinoma in vitro model

Ostrowska,

Rawłuszko-Wieczorek,

Ostapowicz

et al. 2024

Front. Oncol.

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BackgroundRNA methyltransferase-like 3 (METTL3) is responsible for methyl group transfer in the progression of N6-methyladenosine (m6A) modification. This epigenetic feature contributes to the structural and functional regulation of RNA and consequently may promote tumorigenesis, tumor progression, and cellular response to anticancer treatment (chemo-, radio-, and immunotherapy). In head and neck squamous cell carcinoma (HNSCC), the commonly used chemotherapy is cisplatin. Unfortunately, cisplatin resistance is still a major cause of tumor relapse and patients’ death. Thus, this study aimed to investigate the role of METTL3 on cellular response to cisplatin in HNSCC in vitro models.Materials and methodsHNSCC cell lines (H103, FaDu, and Detroit-562) with stable METTL3 knockdown (sgMETTL3) established with CRISPR-Cas9 system were treated with 0.5 tolerable plasma level (TPL) and 1 TPL of cisplatin. Further, cell cycle distribution, apoptosis, CD44/CD133 surface marker expression, and cell’s ability to colony formation were analyzed in comparison to controls (cells transduced with control sgRNA).ResultsThe analyses of cell cycle distribution and apoptosis indicated a significantly higher percentage of cells with METTL3 knockdown 1) arrested in the G2/S phase and 2) characterized as a late apoptotic or death in comparison to control. The colony formation assay showed intensified inhibition of a single cell’s ability to grow into a colony in FaDu and Detroit-562 METTL3-deficient cells, while a higher colony number was observed in H103 METTL3 knockdown cells after cisplatin treatment. Also, METTL3 deficiency significantly increased cancer stem cell markers’ surface expression in all studied cell lines.ConclusionOur findings highlight the significant influence of METTL3 on the cellular response to cisplatin, suggesting its potential as a promising therapeutic target for addressing cisplatin resistance in certain cases of HNSCC.

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Suppression of head and neck cancer cell survival and cisplatin resistance by GRP78 small molecule inhibitor YUM70

Cited by 6 publications

References 44 publications

Phase 2 Study of Sorafenib, Valproic Acid, and Sildenafil in the Treatment of Recurrent High-Grade Glioma

Phase 2 Study of Sorafenib, Valproic Acid, and Sildenafil in the Treatment of Recurrent High-Grade Glioma

GRP78 Inhibitor YUM70 Suppresses SARS-CoV-2 Viral Entry, Spike Protein Production and Ameliorates Lung Damage

The two-faced role of RNA methyltransferase METTL3 on cellular response to cisplatin in head and neck squamous cell carcinoma in vitro model

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