In addition to EGFR other receptor tyrosine kinases
In addition to EGFR, other receptor tyrosine kinases (RTKs) also play roles in the tumor progression under hypoxia, especially hepatocyte growth factor receptor (cMet) (Le et al., 2012). Our data suggested that unlike EGFR, hypoxia had no apparent effect on cMet Emodepside (data not shown), suggesting that hypoxia play a receptor-specific role in regulation of the RTKs’ expression. Taken together, in this study, our results suggested that under hypoxia, cell type and density determine the change of EGFR expression, which regulates cell survival and radiosensitivity.
Conflict of interest
Acknowledgements This work was supported by grantsfrom the National Natural Science Foundation of China (81703034, 31600679), the Project of Science and Technology Department of Jilin Province (20090458), the Project of Health and Family Planning Commission of Jilin Province (2014ZC054), the Bethune Special Research of Science and Technology Department of Jilin Province (20160101079JC), and the Horizontal Project of Jilin University (2015373).
Introduction Non–small-cell lung cancer (NSCLC) is the predominant type of lung cancer, which is the most common cause of cancer deaths worldwide (Siegel et al., 2015). Epidermal growth factor receptor (EGFR)–mediated signaling is the major driver of NSCLC (Pao and Chmielecki, 2010), and EGFR is known to be highly expressed or mutated in about 60% of NSCLC patients (Sharma et al., 2007). Therefore, inhibition of EGFR signaling has been actively explored for its therapeutic potential against NSCLC. Targeted treatment using EGFR tyrosine kinase inhibitors (TKIs) has led to dramatic clinical improvement in NSCLC patients harboring EGFR mutations (Fukuoka et al., 2003). However, resistance to TKI treatment develops in most patients owing to the development of secondary mutations in EGFR (Pao and Chmielecki, 2010). Thus, new agents that can effectively counteract acquired TKI resistance are urgently needed. The phytochemical sulforaphane (SFN), first identified in broccoli sprouts and present in high concentrations in most cruciferous vegetables (Whiteside et al., 2013), has been shown to modulate multiple targets involved in cancer development (Bayat Mokhtari et al., 2017). SFN activates different signaling pathways by inducing the production of reactive oxygen species (ROS), producing DNA damage, cell-cycle arrest, and/or cell death in many cancer cell lines (Choi et al., 2008, Clarke et al., 2011, Jo et al., 2014, Moon et al., 2009, Park et al., 2014, Singh et al., 2005, Wang et al., 2015, Wu et al., 2016). Depending on the cancer cell type studied, the effects of SFN can be very diverse and include inhibition of cell growth, invasion, and cell-cycle progression (Choi et al., 2008, Jo et al., 2014, Kim et al., 2006, Moon et al., 2009, Park et al., 2014, Singh et al., 2005, Wang et al., 2015, Wu et al., 2016). In addition, SFN has been shown to display differential cytotoxicity against prostate and breast cancer cell lines compared with normal prostate and mammary epithelial cells (Clarke et al., 2011, Telang et al., 2009). Thus, whereas SFN is known to induce the production of ROS, the basis for the differential inhibitory effects of SFN on different cell types remains poorly understood. SFN has been demonstrated to be an anti-NSCLC agent (Jeong et al., 2017, Lin et al., 2017, Mi et al., 2007, Tripathi et al., 2015, Wang et al., 2017). In evaluating the potential of SFN to treat TKI-resistant NSCLC, we recently found that SFN inhibits EGFR expression and effectively inhibits the growth of EGFR-TKI–resistant NSCLC cells and tumors derived from them (Chen et al., 2015). Interestingly, the antitumor activity of SFN against TKI-resistant NSCLC cells harboring mutant EGFR was greater than that against wild-type EGFR NSCLC cells (Chen et al., 2015). This suggests the possibility that EGFR status in different cells may be a factor in governing the cell's sensitivity to SFN. Since more than 45% of NSCLCs exhibit EGFR overexpression (Herbst et al., 2008), it is important to know whether high levels of EGFR affect SFN sensitivity. Here, we examined whether ROS production is involved in the inhibition of EGFR signaling by SFN and whether the level of EGFR in NSCLC cells affects sensitivity to SFN.