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  • 4-Phenylbutyric acid br Activation of ERK is involved in BPS

    2020-08-18


    3.6. Activation of ERK1/2 is involved in BPS induced activation of TGF-β/ Smad2/3 signal
    It has been reported that activation of ERK1/2, JNK, and p38-MAPK can regulate the transcription of TGF-β in cancer 4-Phenylbutyric acid (Xiao et al., 2008). We pre-treated A549 and H1299 cells with the inhibitors of ERK1/2, JNK, and p38-MAPK and then further treated cells with 10 nM BPS. Our data indicated that the ERK1/2 inhibitor PD98054, while not the two others, can attenuate BPS induced upregulation of TGF-β in both A549 (Fig. 6 A) and H1299 (Fig. 6 B) cells. Further, ERK1/2 in-hibitor PD98054 can attenuate BPS induced phosphorylation of SMAD2/3 in A549 cells (Fig. 6 C). Western blot analysis showed that BPS can increase the phosphorylation of ERK1/2 in both A549 and H1299 cells (Fig. 6 D). These results suggested that activation of ERK1/ 2 is involved in BPS induced activation of TGF-β/Smad2/3 signal.
    4. Discussion
    Although numerous studies indicated that BPA can trigger the mi-gration and invasion of cancer cells including lung cancer cells (Rochester and Bolden, 2015; Zhang et al., 2014), the roles of its ana-logue BPS on cancer development are not well illustrated. Our present study revealed that nanomolar concentration of BPS can trigger the in vitro migration of NSCLC cells. BPS can increase the expression of TGF-
    β and then activate Smad2/3 pathways. Targeted inhibition of TGF-β/ Smad2/3 can abolish BPS induced migration of NSCLC cells. Further, BPS activates TGF-β/Smad2/3 via activation of ERK1/2, while ERα/β or GPER was not involved in this process. Collectively, we identified that BPS can trigger the migration of NSCLC cells via ERK1/2 mediated activation of TGF-β/Smad2/3 signals.
    The biological effects of BPS were not fully understood. One recent study showed that nanomolar concentrations of BPS can trigger the in vitro migration and invasion of triple negative breast cancer (TNBC) cells (Deng et al., 2018). Similarly, few studies also suggested that BPS can trigger epithelial mesenchymal transition (EMT) of cancer cells via ER dependent manner (Kim et al., 2017). BPS can induce oxidative stress and damage in human red blood cells (Macczak et al., 2017). Low dose of BPS exposure during perinatal period can alter the development of female mouse mammary gland (Kolla et al., 2018). BPS can induce the production of caspase 8 and alter the cellular apoptotic and survival signaling (Salvesen and Walsh, 2014). Considering that BPS had equivalent or greater estrogenic potency to E2 when assayed in mem-brane receptor models (Vinas and Watson, 2013), the safety issues about BPS on human need further study.
    We found that ERK1/2 mediated activation of TGF-β/Smad2/3 signals was involved in BPS induced migration of NSCLC cells. TGF-β/ Smad2/3 signals have been well illustrated to regulate the development of NSCLC via promoting cancer cell motility, invasiveness and metas-tasis (Moustakas and Heldin, 2009). The upregulation of TGF-β in NSCLC patients was correlated with poor prognosis and tumor metas-tasis (Chen et al., 2014). Similarly, BPA can regulate the TGF-β gen-eration to modulate the proliferation of urine leiomyoma cells (Shen et al., 2018). Although GPER has been reported to mediate the stimu-lation effects of BPS on migration of breast cancer cells (Deng et al., 2018), targeted inhibition of either ERα/β or GPER had no effect on BPS induced migration of NSCLC cells. However, blocking ERK1/2 can attenuate BPS induced cell migration and activation of TGF-β/Smad2/3 signals, which was consistent with previous studies that inhibition of ERK1/2 can impair the expression of TGF-β and its promotion effects on  Toxicology in Vitro 54 (2019) 224–231
    cancer development (Derynck et al., 2014; Sritananuwat et al., 2017). The mechanisms responsible for BPS induced activation of ERK1/2 need further investigation.
    In conclusion, we found that nanomolar BPS can trigger the mi-gration of NSCLC cells via activation of TGF-β/Smad2/3 signals. This process is mediated by BPS induced activation of ERK1/2 while not ERα/β or GPER. Therefore, BPS exposure might be a potential risk factor for the development of NSCLC.
    Conflict of interest
    The authors declare no conflict of interest.
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