Lycopene Protects Keratinocytes Against UVB Radiation-Induced Carcinogenesis via Negative Regulation of FOXO3a Through the mTORC2/AKT Signaling Pathway
Authors: Shina Xu
Ping Chen
Jinlong Qu
Journal: Journal of Cellular Biochemistry (2018)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: CARCINOGENESIS; FOXO3a; KERATINOCYTES; LYCOPENE; mTORC2/AKT.
Affiliations: Department of Pharmacy, Affiliated Hospital of Shandong Medical College, Linyi, 276000, Shandong Province, China., Department of Dermatology, Linyi Central Hospital, Yishui County, Linyi, 276400, Shandong Province, China.

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 cyclin-dependent 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. J. Cell. Biochem. 119: 366-377, 2018. © 2017 Wiley Periodicals, Inc. 

Retracted: No

PubPeer comments:
  Fig. 4 Role of FoxO3a in lycopene-induced cell proliferation and cell apoptosis in HaCaT cells. HaCaT cells were treated with lycopene (1mg ml) for 24 h and cell apoptosis was determined by flow cytometry as described previously (A) . ![file] I have color-coded these moose portraits to highlight the similarities to Fig 2E of [Zhang et al (2017)] .  Flow cytometry was performed to determine the percentages of apoptosis in SW1990 and PANC-1 cells . ![file] Light brown and light purple boxes also facilitate comparison with Fig 2G of [Gao et al (2017)] ,  Cell apoptosis was measured by flow cytometry . ![] The scarlet-boxed moose portrait also appears in Figs 3A from [Fan et al (2018)] and 2C from [Li et al (2018)] . ![] , 
  Fig. 2 Effect of lycopene and UVB on cell apoptosis: representative examples of annexin V-FITC dot-plot with gating for HaCaT cells (A). ![file] I have color-coded these strawberries to indicate their manifestations in previous and subsequent papers by otherwise-unrelated authors. See Fig 5D of [Zhang et al (2017)] for the red, blue, green, light orange panels, although the two red-boxed panels here have seen some selective disappearance of points. ![file] Pink-boxed panel (and also red again) appear in Fig 2C of [Li et al (2016)] , and in a number of other papers linked in that thread. ![] The two panels in the brown box at right are both versions of a panel in Fig 2G of [Li et al (2018)] , and Fig 3A from [Long et al (2017)] . ![] ![] , 
 Fig 3C,  Immunofluorescence (60u00d7magnification) of FOXO3a (green) and DAPI (blue) of HaCaT with lycopene treatment or no treatment . ![file] ,