Department of Colorectal and Anal Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan City, Shandong Province, China.
Department of Hepatobiliary Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan City, Shandong Province, China.
J Biochem Mol Toxicol. 2021 Mar;35(3):e22665. doi: 10.1002/jbt.22665. Epub 2020 Dec 28.
Colorectal cancer (CRC) is the leading type of diagnosed cancer; globally, it resides in the fourth-leading origin of cancer-interrelated mortality in the globe. The treatment strategies were chemotherapy and potent radiotherapy. Although chemotherapy treatment can eliminate tumor cells, it remains with unnecessary toxic effects in cancer patients. Therefore, the identification of natural-based compounds, which have selectively inhibiting target proteins with limited toxicity that can facilitate the therapeutic approaches against CRC. In this existing approach, which highlights the binding efficacy of our anthraquinone compound, purpurin against phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) protein restrains the CRC cell growth by inhibiting phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT), cell proliferation, and inducing apoptosis signaling. Primarily, purpurin (36 μM) exposed to HCT-116 cells and incubated for 24 and 48 h could induce reactive oxygen species production, subsequently alter mitochondrion membrane, and increase the apoptotic cells in HCT-116. LHPP, a kind of histidine phosphatase protein, has been considered as a tumor suppressor in numerous carcinomas. However, purpurin-mediated LHPP proteins and its associated molecular events in CRC remain unclear. In our docking studies revealed that purpurin has been strongly interacts with LHPP via hydrophobic and hydrophilic binding interaction. Western blot results confirmed that purpurin enhances the expression of LHPP protein, thereby inhibits the expression of phosphorylated-PI3K/AKT, EGFR, cyclin-D1, PCNA in HCT-116 cells. Moreover, purpurin induces messenger RNA expression of apoptotic genes (Bax, CASP-9, and CASP-3) in HCT-116 cells. Thus, we conclude that purpurin could be a natural and useful compound, which inhibits the growth of CRC cells through the activation of LHPP proteins.
结直肠癌（CRC）是最常见的癌症类型；在全球范围内，它是全球癌症相关死亡率第四大的癌症。治疗策略包括化疗和强力放疗。虽然化疗可以消除肿瘤细胞，但它在癌症患者中仍存在不必要的毒性作用。因此，鉴定具有选择性抑制目标蛋白、毒性有限的天然化合物，可以促进针对 CRC 的治疗方法。在这种现有方法中，突出了我们蒽醌化合物 purpurin 与磷酸丝氨酸磷酸组氨酸无机焦磷酸磷酸酶（LHPP）蛋白的结合效力，通过抑制磷脂酰肌醇-3-激酶/蛋白激酶 B（PI3K/AKT）、细胞增殖和诱导细胞凋亡信号来抑制 CRC 细胞生长。首先，将 purpurin（36μM）暴露于 HCT-116 细胞中，并孵育 24 和 48 小时，可以诱导活性氧的产生，随后改变线粒体膜，并增加 HCT-116 中的凋亡细胞。LHPP 是一种组氨酸磷酸酶蛋白，已被认为是许多癌中的肿瘤抑制因子。然而，purpurin 介导的 LHPP 蛋白及其在 CRC 中的相关分子事件尚不清楚。在我们的对接研究中发现，purpurin 与 LHPP 之间存在强烈的相互作用，通过疏水和亲水结合相互作用。Western blot 结果证实，purpurin 增强了 LHPP 蛋白的表达，从而抑制了 HCT-116 细胞中磷酸化-PI3K/AKT、EGFR、细胞周期蛋白 D1、PCNA 的表达。此外，purpurin 诱导 HCT-116 细胞中凋亡基因（Bax、CASP-9 和 CASP-3）的信使 RNA 表达。因此，我们得出结论，purpurin 可能是一种天然有用的化合物，通过激活 LHPP 蛋白抑制 CRC 细胞的生长。
