Far-infrared irradiation inhibits proliferation of human upper airway epithelial cells by protein phosphatase 2A-promoted dephosphorylation of p70 S6 kinase

다국어 초록 (Multilingual Abstract)

Far-infrared (FIR) ray is an invisible electromagnetic radiation with a wavelength of 3‒1000 μm and conveys photon energy range of 12.4 meV to 1.7 eV. When living organisms and cells are exposed to FIR rays, they elicit various biological effects, including vasorelaxation and inhibition of cell proliferation. Functional dysregulation of airway epithelial cells caused by pathogen infections (such as viruses), toxicants, and allergens contributes to the development and exacerbation of chronic rhinosinusitis, asthma, and nasal polyposis, ultimately resulting in airway narrowing caused by epithelial hyperplasia and/or hypertrophy. Although these otolaryngological diseases are common worldwide, the effect of FIR irradiation remains to be elucidated. Therefore, in the present study, I investigated the molecular mechanisms through which FIR irradiation inhibits the proliferation of upper airway epithelial cells. FIR irradiation for 30 min significantly inhibited the proliferation of NCI-H292 cells with no alteration in cell death. The anti-proliferative effect of FIR radiation was accompanied by decreased phosphorylation of p70S6K at Thr389 (p-p70S6K-Thr389), with no changes in the phosphorylation of mTOR at Ser2448 (p-mTOR-Ser2448) and AMPK at Thr172 (p-AMPK-Thr172). As hypothesized, ectopic expression of dn-AMPKα1 gene did not affect FIR irradiation-decreased cell proliferation and p-p70S6K-Thr389. Overexpression of p70S6K-T389E mutant gene significantly reversed FIR irradiation-inhibited p-p70S6K-Thr389 and cell proliferation. Furthermore, cotreatment with okadaic acid, a specific PP2A inhibitor, significantly restored p-p70S6K-Thr389, and knockdown of PP2Ac gene expression by siRNA almost completely reversed p-p70S6K-Thr389 and cell proliferation. I examined whether FIR irradiation enhanced the binding of p70S6K and PP2Ac because total PP2Ac expression was not altered in FIR-irradiated cells. Coimmunoprecipitation assay results showed that 30 min of FIR irradiation remarkably promoted the physical association of p70S6K and PP2Ac. Hyperthermal stimulus (39 ℃) did not alter the level of p-p70S6K-Thr389 and cell proliferation. Similar to NCI-H292 cells, FIR irradiation for 30 min decreased p-p70S6K-Thr389 and cell proliferation in HNEpCs and HNPEpCs. Furthermore, hyperthermal stimulus (39 ℃) did not affect p-p70S6K-Thr389 and cell proliferation in these cells. My results demonstrated that FIR irradiation for 30 min decreased the proliferation of upper airway epithelial cells through PP2A-mediated inhibition of p70S6K phosphorylation, independent of the hyperthermal effect of FIR radiation. These results suggest that FIR therapy can be used to prevent and treat nasal narrowing diseases including chronic rhinosinusitis, nasal polyposis, and hypertrophy of the nasal turbinate.

목차 (Table of Contents)

• Introduction 1
• Materials and methods 5
• Results 12
• Discussion 37
• Summary 42
• References 44
• Korean abstract 52
• Appendix (abbreviations) 55