Inhibition of mTOR by apigenin in UVB-irradiated keratinocytes: A new implication of skin cancer prevention

Abstract

Ultraviolet B (UVB) radiation is the major environmental risk factor for developing skin cancer, the most common cancer worldwide, which is characterized by a berrant activation of Akt/mTOR (mammalian target of rapamycin). Importantly, the link between UV irradiation and mTOR signaling has not been fully established. Apigenin is a naturally occurring flavonoid that has been shown to inhibit UV-induced skin cancer. Previously, we have demonstrated that apigenin activates AMP-activated protein kinase (AMPK), which leads to suppression of basal mTOR activity in cultured keratinocytes. Here, we demonstrated that apigenin inhibited UVB-induced mTOR activation, cell proliferation and cell cycle progression in mouse skin and in mouse epidermal keratinocytes. Interestingly, UVB induced mTOR signaling via PI3K/Akt pathway, however, the inhibition of UVB-induced mTOR signaling by apigenin was not Akt-dependent. Instead, it was driven by AMPK activation. In addition, mTOR inhibition by apigenin in keratinocytes enhanced autophagy, which was responsible, at least in part, for the decreased proliferation in keratinocytes. In contrast, apigenin did not alter UVB-induced apoptosis. Taken together, our results indicate the important role of mTOR inhibition in UVB protection by apigenin, and provide a new target and strategy for better prevention of UV-induced skin cancer.

Impact on Autophagy and Ultraviolet B Induced Responses of Treatment with the MTOR Inhibitors Rapamycin, Everolimus, Torin 1, and pp242 in Human Keratinocytes

“…Keratinocytes are the major target of UVB-induced skin damage because they serve as the predominant component in the epidermal structure. Bridgeman et al [93] found that UVB radiation activated MTOR signaling in mouse epidermal keratinocytes and in mouse skin. Syed et al [94] reported that UVB can increase MTOR phosphorylation at 1 hour after radiation.…”

“…Nevertheless, inhibition of MTOR signaling has been observed to have the anticarcinogenesis potentiality in the UVB treated mouse model; for example, Rapamycin or apigenin treatment reduced UVB-induced epidermal proliferation through inhibiting MTOR activation [26, 93], and AZD4547 and Curcumin C3 complex suppressed UVB-induced epidermal hyperplasia via suppressing FGFR/MTOR signaling [96]. Hence, more work is needed to clarify the role of MTOR signaling in the network of UV regulated pathways, especially in the studies in vivo.…”

The Roles of Autophagy and the Inflammasome during Environmental Stress-Triggered Skin Inflammation

“…Autophagy induced by resveratrol could reduce UVB-induced apoptosis in keratinocytes, thus reducing malignant transformation [94]. Other natural components such as disaccharide trehalose and apigenin are also reported that can induce autophagy to against UVB-induced cell death [95,96]. In addition, a natural cyclopeptide, roseotoxin B, has also been demonstrated to trigger autophagy to overcome picryl chlororide-induced contact hypersensitivity in mice [97].…”

Plant Flavone Apigenin: an Emerging Anticancer Agent

“…Aberrant activation of Akt/mTOR characterizes skin cancer development as a result of UVB radiation. Apigenin inhibited UVB-mediated mTOR activation in mouse skin and in mouse epidermal keratinocytes independent of Akt, and this led to autophagy [154]. Using 7,12-dimethyl benz[a]anthracene (DMBA)-induced experimental oral carcinogenesis golden hamsters buccal pouch model by painting 0.5% DMBA three times a week for 14 weeks, Silvan et al [155] demonstrated that oral administration of 2.5 mg/kg apigenin reduced tumor volume causing inhibition of cell proliferation, apoptosis inflammation, and angiogenesis markers, and modulation of phase I and II detoxification cascades.…”