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Lidocaine Induces Apoptosis in Head and Neck Squamous Cell Carcinoma Cells Through Activation of Bitter Taste Receptor T2R14

View ORCID ProfileZoey A. Miller, Jennifer F. Jolivert, Ray Z. Ma, Sahil Muthuswami, Arielle Mueller, Derek B. McMahon, View ORCID ProfileRyan M. Carey, View ORCID ProfileRobert J. Lee
doi: https://doi.org/10.1101/2022.11.22.517413
Zoey A. Miller
1Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
2Pharmacology Graduate Group
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Jennifer F. Jolivert
1Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
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Ray Z. Ma
3Harriton High School, Bryn Mawr, PA
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Sahil Muthuswami
1Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
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Arielle Mueller
1Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
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Derek B. McMahon
1Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
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Ryan M. Carey
1Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
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Robert J. Lee
1Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
4Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
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  • For correspondence: rjl@pennmedicine.upenn.edu
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Abstract

Head and Neck Squamous Cell Carcinomas (HNSCCs) have high mortality due to late stage diagnosis, high metastasis rates, and poor treatment options. Current therapies are invasive and aggressive, leading to a severe decline in patient quality of life (QoL). It is vital to create new therapies that are both potent and localized and/or targeted to prolong survival while maintaining QoL. Lidocaine is a local anesthetic used in HNSCC surgery settings. Lidocaine also activates bitter taste (taste family 2) receptor 14 (T2R14). T2Rs are G-protein coupled receptors (GPCRs) that increase intracellular Ca2+ when activated. T2Rs are expressed in mucosal epithelia, including internal regions of the head and neck, and are accessible drug targets. Here, we show that lidocaine increases intracellular Ca2+ and decreases cAMP in several HNSCC cell lines. Ca2+ release from the ER results in Ca2+ uptake into the mitochondria. Ca2+ mobilization is blocked with GPCR inhibitors and T2R14 antagonist, 6-methoxyflavanone. Lidocaine activation of T2R14 depolarizes the mitochondrial membrane, inhibits cell proliferation, and induces apoptosis. Lidocaine activates caspase-3 and -7 cleavage and also increases total caspase protein levels despite no changes in mRNA production. Both total and cleaved caspase products were upregulated even in the presence of cycloheximide, an inhibitor of protein synthesis. This suggests inhibition of the ubiquitin-proteasome system. It is vital to understand Lidocaine-induced apoptosis in HSNCCs to utilize its chemotherapeutic effects as a treatment option. In addition, future studies on T2R14 expression in HNSCC patients could provide insight for implementing lidocaine as a targeted topical therapy.

Competing Interest Statement

The authors have declared no competing interest.

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Posted November 24, 2022.
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Lidocaine Induces Apoptosis in Head and Neck Squamous Cell Carcinoma Cells Through Activation of Bitter Taste Receptor T2R14
Zoey A. Miller, Jennifer F. Jolivert, Ray Z. Ma, Sahil Muthuswami, Arielle Mueller, Derek B. McMahon, Ryan M. Carey, Robert J. Lee
bioRxiv 2022.11.22.517413; doi: https://doi.org/10.1101/2022.11.22.517413
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Lidocaine Induces Apoptosis in Head and Neck Squamous Cell Carcinoma Cells Through Activation of Bitter Taste Receptor T2R14
Zoey A. Miller, Jennifer F. Jolivert, Ray Z. Ma, Sahil Muthuswami, Arielle Mueller, Derek B. McMahon, Ryan M. Carey, Robert J. Lee
bioRxiv 2022.11.22.517413; doi: https://doi.org/10.1101/2022.11.22.517413

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