Abstract
Adrenergic nerve fibers in the tumor microenvironment promote tumor growth and represent a potential target for cancer therapy. However, the effectiveness of targeting adrenergic nerve fibers for oral squamous cell carcinoma (OSCC) therapy needs to be evaluated by preclinical data. Herein, the 4NQO-induced and orthotopic xenograft OSCC mice models were established. We demonstrated that using 6OHDA chemical denervation as well as using nebivolol adrenergic blockade could halt the oral mucosa carcinogenesis. Our preclinical studies suggested that nebivolol, which is widely used to treat cardiovascular diseases, can be repositioned as a potential candidate to treat OSCC. Remarkably, we revealed the precise effect and mechanism of nebivolol on OSCC cells proliferation, cell cycle, and cell death. Administration of nebivolol could activate the endoplasmic reticulum (ER) stress signaling pathway through increasing the expression of inducible nitric oxide synthase, which subsequently triggers the integrated stress response and cell growth arrest. Simultaneously, ER stress also induced mitochondrial dysfunction in OSCC cells. We found that the accumulation of dysfunctional mitochondria with the impaired electron transport chain caused increasing reactive oxygen species production, which ultimately resulted in OSCC cell death. Altogether, our finding suggested a novel therapeutic opportunity for OSCC by targeting adrenergic nerve fibers, and repurposing nebivolol to treat OSCC can be represented as an effective strategy.
Highlights
Oral squamous cell carcinoma (OSCC) is the most common head and neck malignant tumor, which is characterized by poor prognosis, high recurrence rates, and difficult treatment (Erratum, 2020)
In order to determine the distribution of nerve fibers in OSCC tissues, the neuromarker β-III-tubulin was used as the target protein
IHC experiments were performed on the pathological tissue sections of the patients who had been clinically diagnosed with OSCC or OLK
Summary
Oral squamous cell carcinoma (OSCC) is the most common head and neck malignant tumor, which is characterized by poor prognosis, high recurrence rates, and difficult treatment (Erratum, 2020). The major therapeutic strategy for OSCC cells is surgery plus radiotherapy or chemotherapy (Zhang et al, 2020). The component from the tumor microenvironment (TME) may serve as a potential drug target in the treatment of cancer. Inside the TME, nerves are emerging as regulators to affect cancer initiation, progression, and metastasis. Some pioneer studies have shown that autonomic nerve fibers could regulate tumor progression by secreting neurotransmitters, which could bind with the corresponding receptors on the surface of tumor cell membranes (Zahalka and Frenette, 2020). The newly discovered role of nerves in regulating cancer progression offers an opportunity to develop therapeutic strategies. Adrenergic stimulation provides opportunities for repurposing β-blockers to OSCC therapy
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