Department of Biochemistry, University of Hyderabad, Hyderabad, 500046, Telangana, India.
Sci Rep. 2017 Jun 19;7(1):3831. doi: 10.1038/s41598-017-03940-1.
Stress induced BSA (bovine serum albumin) protein aggregation is effectively mitigated in vitro by TUDCA (tauroursodeoxycholic acid) than by PBA (4- phenylbutyric acid), chemical chaperones approved by FDA for the treatment of biliary cirrhosis and urea cycle disorders respectively. TUDCA, unlike PBA, enhances trypsin mediated digestion of BSA. TUDCA activates PERK, an ER-resident kinase that phosphorylates the alpha-subunit of eukaryotic initiation factor2 (eIF2α) and promotes the expression of activated transcription factor 4 (ATF4) in HepG2 cells. In contrast, PBA induced eIF2α phosphorylation is not mediated by PERK activation and results in low ATF4 expression. Neither chaperones promote expression of BiP, an ER chaperone, and CHOP (C/EBP homologous protein), downstream target of eIF2α-ATF4 pathway. Both chaperones mitigate tunicamycin induced PERK-eIF2α-ATF4-CHOP arm of UPR and expression of BiP. TUDCA, unlike PBA does not decrease cell viability and it also mitigates tunicamycin, UV-irradiation and PBA induced PARP (poly ADP-ribose polymerase) cleavage and cell death. These findings therefore suggest that TUDCA's antiapoptotic activity to protect HepG2 cells and PBA's activity that limits tumor cell progression may be important while considering their therapeutic potential.
牛血清白蛋白（BSA）在应激条件下容易发生聚集，而 TUDCA（牛磺熊脱氧胆酸）比 PBA（4- 苯基丁酸）能更有效地减轻这种聚集，这两种化合物都是 FDA 批准用于治疗胆汁性肝硬化和尿素循环障碍的化学伴侣。与 PBA 不同，TUDCA 能增强胰蛋白酶对 BSA 的消化作用。TUDCA 激活 PERK，这是一种内质网驻留激酶，可使真核起始因子 2 的 α 亚基磷酸化，并促进 HepG2 细胞中激活转录因子 4（ATF4）的表达。相比之下，PBA 诱导的 eIF2α 磷酸化不是通过 PERK 激活介导的，导致 ATF4 表达水平较低。两种伴侣蛋白都不能促进内质网伴侣蛋白 BiP 和 eIF2α-ATF4 通路下游靶标 C/EBP 同源蛋白（CHOP）的表达。两种伴侣蛋白都能减轻衣霉素诱导的 PERK-eIF2α-ATF4-CHOP 通路和 BiP 的表达。与 PBA 不同，TUDCA 不会降低细胞活力，它还能减轻衣霉素、UV 照射和 PBA 诱导的多聚（ADP-核糖）聚合酶（PARP）裂解和细胞死亡。因此，这些发现表明，TUDCA 具有保护 HepG2 细胞的抗凋亡活性，而 PBA 限制肿瘤细胞进展的活性，在考虑它们的治疗潜力时可能很重要。
