• 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2020-03
  • 2020-07
  • 2020-08
  • 2021-03
  • br We noted that atalantraflavone treatment may


    We noted that atalantraflavone treatment may facilitate cellular apoptosis in cisplatin resistant NSCLC Epoprostenol with massively observable cleaved forms of PARP and caspase-3. The sub-G1 fraction and apoptotic rates were evidently increased with atalantraflavone treatment. In current research, we found that Twist1 stability was affected by atalantraflavone. Previous work showed that Twist1 can be phosphorylated at Serine 68 or Serine 42 by mitogen-activated protein kinases (MAPKs) and Akt, respectively [10, 15]. These posttranslational modifications may stabilize Twist1 and subsequently inhibit apoptosis [10, 15]. Therefore, Twist1 abundance is negatively correlated with apoptosis. We anticipated that atalantraflavone may promote apoptosis of NSCLC cells via its regulatory role upon Twist1 protein.
    The EMT is a process in which cancerous cells acquire properties of mesenchymal cells whereas the epithelial features are lost [16]. EMT has been shown to promote invasion, survival of disseminated tumor cells and local formation of metastasis [16]. EMT is also related to the generation of cancer stem cells and therefore EMT can contribute to the stemness during cancer progression [17]. Apart from direct transcriptional repression of E-cadherin, Twist1 also binds Cullin2 (Cul2) promoter and upregulates Cul2 circular RNA expression to induce vimentin expression [18]. Li et al. showed that Twist1 is capable of potentiating the interaction between p53 and MDM2 to facilitate MDM2 mediated p53 degradation [19]. Twist1 and Bmi1 are also associated with the proximal regions of E-cadherin and p16INK4a promoter and cooperate to inhibit EMT process [20]. Notably, overexpression of Twist1 in cancer cells may lead to the acquisition of EMT features with enhanced migratory or invasive abilities [20]. All these data have suggested that Twist1 is significantly associated with EMT and metastatic characteristics of cancer cells. O ur experimental results have proved that atalantraflavone favors Twist1 degradation in NSCLC cells. By regulating the stability of Twist1 protein, we argue that atalantraflavone administration might be an effective strategy to markedly eliminate endogenous Twist1 and inhibit NSCLC progression. Notably, lowering the drug concentrations used in treatment of cancer cells may decrease the risk of non-specific side effects [21]. Importantly, we noted that Twist1 overexpression could partially reverse the effect of AFL treatment implying that there might be stoichiometric balance between AFL and Twist1. Therefore, chemical modifications of atalantraflavone might be required to increase cellular sensitivity to agents and guarantee the safety. In addition, cancer cells usually adapt to pharmaceutic intervention, acquire decreased sensitivity to the initial treatment and become resistant to drugs [21]. Whether atalantraflavone could display long- lasting effect on NSCLC inhibition deserves further investigation.
    We have demonstrated that atalantraflavone indeed affects Twist1 protein turnover via proteasomal degradation. Previous report showed that BTRC is a
    candidate E3 ligase for Twist1 and BTRC colocalizes with Twist1 in the nucleus [22]. A recent report postulated that PAQR3 could form a complex with Twist1 and BTRC and therefore enhance BTRC-Twist1 binding and Twist1 degradation [23]. Whether BTRC and other ubiquitin ligases are involved in atalantraflavone mediated regulation of Twist1 remain an open question. Intricate experimental design should be performed to fully address these possibilities.
    5. Conclusions
    Collectively, we have identified a novel function of atalantraflavone to inhibit NSCLC progression. The natural product atalantraflavone accelerates Twist1 degradation via enhanced Twist1 ubiquitination. Since acquisition of drug resistance is a primary obstacle during cancer treatment and Twist1 depletion can elevate NSCLC sensitivity to cisplatin [24], treatment with atalantraflavone may overcome cisplatin resistance and present a promising way to eradicate lung cancer cells.