Abstract
The β2-Adrenergic receptor (β2-AR) is a G protein-coupled receptor (GPCR), involved in the development of many cancers, among which HNSCC. In this contest, β2-AR signaling interacts with different pathways, such as PI3K and MAPK, commonly activated by TK receptors. For this reason, TK blockade is one of the most adopted therapeutic strategies in HNSCC patients. In our study we investigated the effects of the β2-AR blocking in HNSCC cell lines, using the selective inhibitor ICI118,551 (ICI), in combination with the MAPK inhibitor U0126. We found that ICI leads to the blocking of p38 and NF-kB oncogenic pathways, strongly affecting also the ERK and PI3K pathways. Cotreatment with U0126 displays a synergic effect on cell viability and pathway alteration. Interestingly, we found that the β2-AR blockade affects Nrf2-Keap1 stability and its nuclear translocation leading to a drastic ROS increase and oxidative stress. Our results are confirmed by a TCGA dataset analysis, showing that NFE2L2 gene is commonly overexpressed in HNSC, and correlated with a lower survival rate. In our system, the PI3K pathway inhibition culminated in the blocking of pro-survival autophagy, a mechanism normally adopted by cancer cells to became less responsive to the therapies. The mTOR expression, commonly upregulated in HNSC, was reduced in patients with disease-recurrence. It is well known that mTOR has a strong autophagy inhibition effect, therefore its downregulation promoted pro-survival autophagy, with a related increase recurrence rate. Our findings highlight for the first time the key role of β2-AR and related pathway in HNSCC cell proliferation and drug resistance, proposing it as a valuable therapeutic molecular target.
Highlights
The β2-Adrenergic receptor (β2-AR) is a G proteincoupled receptor (GPCR), which belongs to the superfamily of adrenergic receptors
Several studies thoroughly described the ERK/mitogen-activated protein kinases (MAPKs) pathway, that is mainly activated by tyrosine kinase receptors (RTK), such as EGFR, and that is over-activated in melanoma, colon, head and neck and breast (HER2+) cancers[8,9,10]
It is well-known that the PI3K/Akt/mTOR and MAPK axis can directly affect the nuclear translocation of Nrf[2], the master regulator of the oxidative stress response[37]
Summary
Β2-AR blockade impairs HNSCC cell viability and has a synergistic effect with the MEK1/2 inhibitor. The combination of drugs leads to a higher ROS production, confirming, that the blockade of both pathways increased the above effect when compared to single treatments It is well-known that the PI3K/Akt/mTOR and MAPK axis can directly affect the nuclear translocation of Nrf[2], the master regulator of the oxidative stress response[37]. We observed that the treatment of UMSCC103 cells with the autophagosome formation inhibitor 3-MA, increased the effect of ICI and U0126 combination This event suggests that autophagy can be considered as a protective mechanism that is employed by cancer cells to overcame drug cytotoxicity. We found that mTOR, which is commonly upregulated in HNSC42, was expressed at low levels in patients with disease-recurrence. mTOR is an autophagy inhibitor and its downregulation in recurrent patients is potentially due to the protective role of autophagy that is reported in our study
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