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.