Abstract
Receptor tyrosine kinases are key regulators of cellular growth and proliferation. Dysregulations of receptor tyrosine kinases in cancer cells may promote tumorigenesis by multiple mechanisms including enhanced cell survival and inhibition of cell death. Araguspongines represent a group of macrocyclic oxaquinolizidine alkaloids isolated from the marine sponge Xestospongia species. This study evaluated the anticancer activity of the known oxaquinolizidine alkaloids araguspongines A, C, K and L, and xestospongin B against breast cancer cells. Araguspongine C inhibited the proliferation of multiple breast cancer cell lines in vitro in a dose-dependent manner. Interestingly, araguspongine C-induced autophagic cell death in HER2-overexpressing BT-474 breast cancer cells was characterized by vacuole formation and upregulation of autophagy markers including LC3A/B, Atg3, Atg7, and Atg16L. Araguspongine C-induced autophagy was associated with suppression of c-Met and HER2 receptor tyrosine kinase activation. Further in-silico docking studies and cell-free Z-LYTE assays indicated the potential of direct interaction between araguspongine C and the receptor tyrosine kinases c-Met and HER2 at their kinase domains. Remarkably, araguspongine C treatment resulted in the suppression of PI3K/Akt/mTOR signaling cascade in breast cancer cells undergoing autophagy. Induction of autophagic death in BT-474 cells was also associated with decreased levels of inositol 1,4,5-trisphosphate receptor upon treatment with effective concentration of araguspongine C. In conclusion, results of this study are the first to reveal the potential of araguspongine C as an inhibitor to receptor tyrosine kinases resulting in the induction of autophagic cell death in breast cancer cells.
Highlights
Receptor tyrosine kinases (RTKs) are key regulators of critical cellular processes including cell growth, differentiation, survival, and repair [1]
Two day treatment of BT-474 cells resulted in antiproliferative activity and inhibition of breast cancer cell growth
Given the critical role of RTKs in controlling cell survival and death in response to external stimuli, we investigated the potential that araguspongine C-induced autophagic death to be associated with suppression of c-Met and/or HER2 signaling in BT-474 cancer cells
Summary
Receptor tyrosine kinases (RTKs) are key regulators of critical cellular processes including cell growth, differentiation, survival, and repair [1]. Multiple RTKs were identified for their oncogenic potential in breast cancer. It is well-established that aberrations in epidermal growth factor (EGF). Receptor and HER2 signaling are associated with worse prognosis and more aggressive phenotypes of breast cancer [2]. Increased expression of c-Met has been detected in human breast cancer and is associated with poor prognosis [3]. RTKs are often selectively altered on malignant cells. They represent attractive targets for cancer therapy, with a number of agents already approved for clinical use [4]
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