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

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, ?-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 ?2-adrenergic receptor (?2AR) expression, concordant with significantly heightened mitochondrial metabolism, as compared with the parental model from which it spontaneously derived. ?-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 ?-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 ?2AR expression. These data implicate ?2AR as a modulator of mitochondrial metabolism and disease progression in HPV(?+?) HNSCC, and warrant further investigation into the use of ?-blockers as low cost, relatively tolerable, complementary treatment options in the clinical management of this disease.

SUBMITTER: Lucido CT 

PROVIDER: S-EPMC6175933 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature