title: Inhibition of EGFR-AKT axis results in the suppression of ovarian tumors in vitro and in preclinical mouse model.
abstract: Ovarian cancer is the leading cause of cancer related deaths in women. Genetic alterations including overexpression of EGFR play a crucial role in ovarian carcinogenesis. Here we evaluated the effect of phenethyl isothiocyanate (PEITC) in ovarian tumor cells in vitro and in vivo. Oral administration of 12 µmol PEITC resulted in drastically suppressing ovarian tumor growth in a preclinical mouse model. Our in vitro studies demonstrated that PEITC suppress the growth of SKOV-3, OVCAR-3 and TOV-21G human ovarian cancer cells by inducing apoptosis in a concentration-dependent manner. Growth inhibitory effects of PEITC were mediated by inhibition of EGFR and AKT, which are known to be overexpressed in ovarian tumors. PEITC treatment caused significant down regulation of constitutive protein levels as well as phosphorylation of EGFR at Tyr1068 in various ovarian cancer cells. In addition, PEITC treatment drastically reduced the phosphorylation of AKT which is downstream to EGFR and disrupted mTOR signaling. PEITC treatment also inhibited the kinase activity of AKT as observed by the down regulation of p-GSK in OVCAR-3 and TOV-21G cells. AKT overexpression or TGF treatment blocked PEITC induced apoptosis in ovarian cancer cells. These results suggest that PEITC targets EGFR/AKT pathway in our model. In conclusion, our study suggests that PEITC could be used alone or in combination with other therapeutic agents to treat ovarian cancer.
authors.affiliation: Department of Pharmacology and University of Pittsburgh Cancer Institute, University of Pittsburgh, Pennsylvania, United States of America.
authors.forename: Sivakumar
authors.initials: S
authors.lastname: Loganathan
authors.forename: Prabodh K
authors.initials: PK
authors.lastname: Kandala
authors.forename: Parul
authors.initials: P
authors.lastname: Gupta
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Srivastava
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000201:enzymology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D012235:Rhodamines / Q000494:pharmacology
chemical_list: D017304:Annexin A5; D000970:Antineoplastic Agents; D017879:Isothiocyanates; D012235:Rhodamines; C022027:lissamine rhodamine B; C058305:phenethyl isothiocyanate; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt