title: Araguspongine C induces autophagic death in breast cancer cells through suppression of c-Met and HER2 receptor tyrosine kinase signaling.
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.
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, USA. mohamedreda_pharmacy@yahoo.com.
authors.forename: Mohamed R
authors.initials: MR
authors.lastname: Akl
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan. nmayoub@just.edu.jo.
authors.forename: Nehad M
authors.initials: NM
authors.lastname: Ayoub
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, USA. hassanyahia_1982@yahoo.com.
authors.forename: Hassan Y
authors.initials: HY
authors.lastname: Ebrahim
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, USA. mohyelmm@warhawks.ulm.edu.
authors.forename: Mohamed M
authors.initials: MM
authors.lastname: Mohyeldin
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Health Sciences Center, Kuwait University, Safat 13110, Kuwait. kyorabi@hsc.edu.kw.
authors.forename: Khaled Y
authors.initials: KY
authors.lastname: Orabi
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, USA. A_foudah@hotmail.com.
authors.forename: Ahmed I
authors.initials: AI
authors.lastname: Foudah
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, USA. elsayed@ulm.edu.
authors.forename: Khalid A
authors.initials: KA
authors.lastname: El Sayed
mesh_terms: D000470:Alkaloids / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011807:Quinolizines / Q000494:pharmacology / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D019859:Proto-Oncogene Proteins c-met; D011807:Quinolizines; D018719:Erb-b2 Receptor Tyrosine Kinases; C455173:araguspongine C; C491743:MET protein, human