[6]-Paradol suppresses proliferation and metastases of pancreatic cancer by decreasing EGFR and inactivating PI3K/AKT signaling
[6]-Paradol suppresses proliferation and metastases of pancreatic cancer by decreasing EGFR and inactivating PI3K/AKT signaling
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[6]-Paradol 通过减少 EGFR 和灭活 PI3K/AKT 信号传导来抑制胰腺癌的增殖和转移
DOI：
10.21203/rs.3.rs-506985/v1
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发表时间：
2021-05
影响因子：
5.8
通讯作者：
Jianxin Jiang
中科院分区：
文献类型：
--
作者：
Xueyi Jiang;Jie Wang;Peng Chen;Zhiwei He;Jian Xu;Yankun Chen;Xinyuan Liu;Jianxin Jiang
背景胰腺癌的发生发展机制尚不清楚，早期转移、复发、耐药和血管侵犯是导致治疗失败的主要原因。探索新的治疗方案是克服耐药性和改善患者预后的必要条件。方法通过体外和体内实验研究[6]-Paradol（6-P）对胰腺癌细胞增殖和转移的影响。通过KEGG富集分析和分子对接分析检测EGFR与6-P的相互作用。采用qRT-PCR检测6-P处理组EGFR mRNA的表达。通过蛋白质印迹法测量PI 3 K/AKT通路的参与。结果6-P能明显抑制胰腺癌细胞的增殖和转移。KEGG富集分析和分子对接分析表明，EGFR与6-P之间存在一定的相互作用，6-P明显降低EGFR蛋白表达水平，但不改变EGFR mRNA表达水平。6-P可通过降低EGFR蛋白的稳定性和增强泛素介导的蛋白酶体依赖性降解而诱导EGFR降解，6-P介导的EGFR降解导致PI 3 K/AKT信号通路失活。然而，EGFR蛋白的异位表达导致对6-P介导的PI 3 K/AKT信号转导的失活的抵抗，并抑制胰腺癌的恶性表型。因此，厄洛替尼可以增强6-P介导的抗癌活性。结论6-P/EGFR/PI 3 K/AKT信号转导轴可能成为胰腺癌治疗的一种新途径。
Background The underlying mechanism behind the tumorigenesis and progression of pancreatic cancer is not clear, and treatment failure is generally caused by early metastasis, recurrence, drug resistance and vascular invasion. Exploring novel therapeutic regimens is necessary to overcome drug resistance and improve patients outcomes. Methods Functional assays were performed to investigate the role of [6]-Paradol (6-P) in proliferation and metastasis of pancreatic cancer in vitro and in vivo. The interaction between EGFR and 6-P was tested by KEGG enrichment analysis and molecular docking analysis. qRT-PCR was performed to detect the mRNA expression of EGFR in 6-P treated groups. Involvement of the PI3K/AKT pathway was measured by western blotting. Results 6-P significantly suppressed pancreatic cancer cell proliferation and metastasis. KEGG enrichment analysis and molecular docking analysis suggested that there existed certain interaction between EGFR and 6-P. In addition, 6-P obviously decreased EGFR protein expression level but did not change the mRNA expression level of EGFR. 6-P could induce degradation of EGFR through decreasing the protein stability of EGFR and enhancing the ubiquitin-mediated proteasome-dependent degradation, 6-P-mediated EGFR degradation led to inactivation of PI3K/AKT signaling pathway. However, ectopic expression of EGFR protein resulted in resistance to 6-P-mediated inactivity of PI3K/AKT signaling and inhibition of malignant phenotype of pancreatic cancer. Inversely, erlotinib could enhance the 6-P-mediated anticancer activity. Conclusion Our data indicated that 6-P/EGFR/PI3K/AKT signaling axis might become one of the potential therapies for the treatment of pancreatic cancer.
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影响因子：
5.3
作者：
通讯作者：
--
DOI：
10.1146/annurev.pathol.3.121806.154305
发表时间：
2021-08
期刊：
Annual review of pathology
影响因子：
--
作者：
A. Maitra;R. Hruban
通讯作者：
A. Maitra;R. Hruban
影响因子：
5.6
作者：
Tsai Y;Xia C;Sun Z
通讯作者：
Sun Z
影响因子：
11.2
作者：
Assi, Mohamad;Achouri, Younes;Jacquemin, Patrick
通讯作者：
Jacquemin, Patrick
影响因子：
3.6
作者：
Hermawan，Adam;Putri，Herwandhani;Utomo，Rohmad Yudi
通讯作者：
Utomo，Rohmad Yudi