Lycopene Protects Keratinocytes Against UVB Radiation‐Induced Carcinogenesis via Negative Regulation of FOXO3a Through the mTORC2/AKT Signaling Pathway

Abstract

Lycopene, one of the most potent anti-oxidants, has been reported to exhibit potent anti-proliferative properties in a wide range of cancer cells through modulation of the cell cycle and apoptosis. Forkhead box O3 (FOXO3a) plays a pivotal role in modulating the expression of genes involved in cell death. Herein, we investigated the role of FOXO3a signaling in the anti-cancer effects of lycopene. Results showed that lycopene pretreatment attenuated UVB-induced cell hyper-proliferation and promoted apoptosis, accompanied by decreased cyclindependent kinase 2 (CDK2) and CDK4 complex in both human keratinocytes and SKH-1 hairless mice. FOXO3a is phosphorylated in response to UVB irradiation and sequestered in the cytoplasm, while lycopene pretreatment rescued this sensitization. Gene ablation of FOXO3a attenuated lycopene-induced decrease in cell hyper-proliferation, CDK2, and CDK4 complex, indicating a critical role of FOXO3a in the lycopene-induced anti-proliferative effect of keratinocytes during UVB irradiation. Transfection with FOXO3a siRNA inhibited the lycopene-induced increase in cell apoptosis, BAX and cleaved PARP expression. Moreover, loss of AKT induced further accelerated lycopene-induced FOXO3a dephosphorylation, while loss of mechanistic target of rapamycin complex 2 (mTORC2) by transfection with RICTOR siRNA induced levels of AKT phosphorylation comparable to those obtained with lycopene. In contrast, overexpression of AKT or mTORC2 decreased the effects of lycopene on the expression of FOXO3a as well as AKT phosphorylation, suggesting that lycopene depends on the negative modulation of mTORC2/AKT signaling. Taken together, our findings demonstrate that the mTORC2/AKT/FOXO3a axis plays a critical role in the anti-proliferative and pro-apoptotic effects of lycopene in UVB-induced photocarcinogenesis.

RETRACTED ARTICLE: Dexmedetomidine attenuates ischemia and reperfusion-induced cardiomyocyte injury through p53 and forkhead box O3a (FOXO3a)/p53-upregulated modulator of apoptosis (PUMA) signaling signaling

“…Forkhead box O3a (FOXO3a), a highly evolutionarily conserved transcription factor, mediates numerous cellular processes, including cell proliferation, cell apoptosis, cell cycle and carcinogenesis [ 16 , 17 ]. p53 and FOXO3a could activate the pro-apoptotic PUMA protein (p53-upregulated modulator of apoptosis), resulting in cell apoptosis and cell cycle arrest [ 18 , 19 ].…”

Lycopene as a Natural Antioxidant Used to Prevent Human Health Disorders

“…Treatment with lycopene decreased UVB-caused cell proliferation while increasing apoptosis via declining CDK2 and CDK4 in hairless SKH-1 mice and human keratinocytes [82]. Moreover, the study conducted on volunteers revealed that lycopene decreased the expression of UVA1 radiation-inducible genes HO-1 upregulation caused by UVA1 and UVA/B [72].…”

“…Furthermore, protein kinase B (AKT) loss can induce more lycopene-caused FOXO3a dephosphorylation, whereas losing the mechanistic target of rapamycin complex 2 (mTORC2) via transfection with a rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR) siRNA induces AKT phosphorylation to amounts like the levels gained by lycopene. On the other hand, AKT/mTORC2 overexpression decreases the lycopene impact on the FOXO3a expression and AKT phosphorylation, indicating the link between lycopene and the mTORC2/AKT signaling negative modulation [82]. Interestingly, lycopene treatment for human breast carcinoma cell line MCF-7 in vitro, leading to cell shrinkage and breakage, is dependent on the dose and time.…”

Lycopene Inhibit IMQ-Induced Psoriasis-Like Inflammation by Inhibiting ICAM-1 Production in Mice

“…Therefore, we know that lycopene, which is the most abundant carotenoid in tomato, may enhance human health benefits in many systems. According to a previous dermatology study, lycopene protects human keratinocytes against full spectrum UVR damage [13]. Although the HaCaT cells immortal, the virtually normal degree of morphologic differentiation was further substantiated by the regular spatial distribution of epidermal differentiation products.…”