Maurya Brajesh K, Trigun Surendra K
Government PG College (Mahatma Gandhi Kashi Vidyapeeth affiliated), Obra, Sonabhadra-231219, India.
Biochemistry Section, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi-221005, India.
Anticancer Agents Med Chem. 2018;18(13):1885-1891. doi: 10.2174/1871520618666171229223335.
Recently, we have reported that Fisetin, a natural flavonol, is able to regress Aflatoxin- B1 (AFB1) induced hepatocellular carcinoma (HCC) by suppressing reactive oxygen species (ROS) led proinflammatory factors in rats. In the current study, we aimed to delineate whether Fisetin does so by modulating the cell growth promoting signaling cascade in HCC. The reciprocal interplay of 3-phosphoinositol kinase (PI3K) vs phosphatase and tensin homologue deleted on chromosome 10 (PTEN) displays Akt, a protein kinase B, to get phosphorylated at Thr308 by a 3-phosphoinositol dependent kinase 1 (PDK1). This commits cells of neoplastic niche to undergo rapid proliferation by p-Akt dependent phosphorylation of glycogen synthase kinase 3β (GSK3β) at Ser 9 position.
In this study, the effect of treatment of 20 mg/kg b.w. Fisetin on relative profile of all these factors were studied in the liver from the HCC rats induced by two doses of 1mg/kg b.w. AFB1 i.p.
As compared to the untreated HCC liver, liver from Fisetin treated HCC group rats showed a significant decline in the activity and level of p-Akt which was consistent with a similar decline in PDK1 level. Concordantly, the level of p-GSK3β was also found to be declined significantly in those Fisetin-treated HCC livers.
A concomitant decline in immunohistochemically detected number of the proliferating cell nuclear antigen (PCNA), a cell proliferation marker, in the HCC liver, further confirmed anti-cell proliferative role of Fisetin during HCC growth . These findings suggest that Fisetin is able to suppress Akt dependent cell growth signaling mechanisms in HCC mainly by down regulating PDK1 dependent Akt phosphorylation.
最近，我们报道了一种天然黄酮醇漆黄素能够通过抑制活性氧（ROS）诱导的大鼠促炎因子，使黄曲霉毒素B1（AFB1）诱导的肝细胞癌（HCC）消退。在当前研究中，我们旨在确定漆黄素是否通过调节HCC中促进细胞生长的信号级联反应来实现这一作用。3-磷酸肌醇激酶（PI3K）与10号染色体缺失的磷酸酶和张力蛋白同源物（PTEN）之间的相互作用，使蛋白激酶B（Akt）在苏氨酸308位点被3-磷酸肌醇依赖性激酶1（PDK1）磷酸化。这使得肿瘤微环境中的细胞通过糖原合酶激酶3β（GSK3β）在丝氨酸9位点的p-Akt依赖性磷酸化而快速增殖。
在本研究中，研究了20mg/kg体重的漆黄素处理对两剂1mg/kg体重腹腔注射AFB1诱导的HCC大鼠肝脏中所有这些因子相对水平的影响。
与未处理的HCC肝脏相比，漆黄素处理的HCC组大鼠肝脏中p-Akt的活性和水平显著下降，这与PDK1水平的类似下降一致。同样，在那些漆黄素处理的HCC肝脏中，p-GSK3β的水平也显著下降。
HCC肝脏中免疫组化检测到的增殖细胞核抗原（PCNA，一种细胞增殖标志物）数量的同时下降，进一步证实了漆黄素在HCC生长过程中的抗细胞增殖作用。这些发现表明，漆黄素能够主要通过下调PDK1依赖性的Akt磷酸化来抑制HCC中Akt依赖性的细胞生长信号机制。
