[6]-Paradol suppresses proliferation and metastases of pancreatic cancer by decreasing EGFR and inactivating PI3K/AKT signaling

Abstract

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.

6-Paradol Alleviates Testosterone-Induced Benign Prostatic Hyperplasia in Rats by Inhibiting AKT/mTOR Axis

“…Activation of AKT signaling was also found to disrupt the balance between Bax and Bcl2 in prostate cell lines [ 49 ]. These findings are also in line with previous reports demonstrating the potential of 6-PD to suppress cell proliferation and inflammation via inactivating AKT/mTOR signaling pathways [ 26 , 27 ]. This is in harmony with the results of the current study as 6-PD was also found to significantly normalize the expression of p-mTOR in the prostatic tissues of testosterone-treated rats.…”

“…These findings were also confirmed by histopathological examination, as 6-PD treatment was associated with significant amelioration of the increase in glandular epithelial height as well as the histopathological signs of prostatic hyperplasia. These observations are in harmony with the anti-proliferative activity of 6-PD reported in several studies [ 24 , 25 , 26 ]. 6-PD was also associated with chemo-preventive effects against buccal pouch carcinogenesis, which can be attributed to its anti-lipid peroxidative and antioxidant activities [ 24 , 35 ].…”

“…6-PD is a pungent compound found in some members of Zingiberaceae , such as ginger ( Zingiber officinale ), and grain of paradise ( Aframomum melegueta ). It possesses a plethora of pharmacological activities including antioxidant, anti-inflammatory, and anti-proliferative actions [ 17 , 18 , 26 ]. Furthermore, 6-PD was shown to inhibit critical pathways for survival including AKT and mTOR [ 27 ].…”

“…Further, it has been shown to possess neuroprotective [ 20 , 21 ], anti-obesity [ 22 ], and anti-ulcerative colitis [ 23 ] actions as well as having the potential to alleviate diabetic neuropathy [ 16 ]. Further, it has proven anti-tumor and anti-proliferative actions [ 24 , 25 , 26 ]. 6-PD can inhibit important survival pathways such as AKT and mTOR [ 27 ].…”

Stereoselective Biocatalyzed Reductions of Ginger Active Components Recovered from Industrial Wastes

“…The possible beneficial properties of ginger, including anticancer and anti-inflammatory activities, have been widely studied [1][2][3][4][5][6][7][8] and generally addressed to non-volatile constituents named gingerols and shogaols (Figure 1a). Recently, other minor compounds, like 6-paradol [9,10] and zingerone [11,12] have shown interesting bioactivity profiles as well. Moreover, ginger is included in the list of 51 medicinal plants identified by The Committee on Herbal Medicinal Products (HMPC) for gastrointestinal disorder treatment (https://www.ema.europa.eu/en/medicines/download-medicine-data).…”