β2-Adrenergic receptor modulates mitochondrial metabolism and disease progression in recurrent/metastatic HPV(+) HNSCC

Christopher T. Lucido, Juan L. Callejas-Valera, Paul L. Colbert, Daniel W. Vermeer, W. Keith Miskimins, William C. Spanos, Paola D. Vermeer

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

The incidence of human papillomavirus-associated head and neck squamous cell carcinoma (HPV[ + ] HNSCC) is rapidly increasing. Although clinical management of primary HPV(+) HNSCC is relatively successful, disease progression, including recurrence and metastasis, is often fatal. Moreover, patients with progressive disease face limited treatment options and significant treatment-associated morbidity. These clinical data highlight the need to identify targetable mechanisms that drive disease progression in HPV(+) HNSCC to prevent and/or treat progressive disease. Interestingly, β-adrenergic signaling has recently been associated with pro-tumor processes in several disease types. Here we show that an aggressive murine model of recurrent/metastatic HPV(+) HNSCC upregulates β2-adrenergic receptor (β2AR) expression, concordant with significantly heightened mitochondrial metabolism, as compared with the parental model from which it spontaneously derived. β-Adrenergic blockade effectively inhibits in vitro proliferation and migratory capacity in this model, effects associated with an attenuation of hyperactive mitochondrial respiration. Importantly, propranolol, a clinically available nonselective β-blocker, significantly slows primary tumor growth, inhibits metastatic development, and shows additive benefit alongside standard-of-care modalities in vivo. Further, via CRISPR/Cas9 technology, we show that the hyperactive mitochondrial metabolic profile and aggressive in vivo phenotype of this recurrent/metastatic model are dependent on β2AR expression. These data implicate β2AR as a modulator of mitochondrial metabolism and disease progression in HPV(+) HNSCC, and warrant further investigation into the use of β-blockers as low cost, relatively tolerable, complementary treatment options in the clinical management of this disease.

Original languageEnglish (US)
Article number81
JournalOncogenesis
Volume7
Issue number10
DOIs
StatePublished - Oct 1 2018

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ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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