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Inhibition of EGFR-AKT axis results in the suppression of ovarian tumors in vitro and in preclinical mouse model

Loganathan, S and Kandala, PK and Gupta, P and Srivastava, SK (2012) Inhibition of EGFR-AKT axis results in the suppression of ovarian tumors in vitro and in preclinical mouse model. PLoS ONE, 7 (8).

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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. © 2012 Loganathan et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Loganathan, S
Kandala, PK
Gupta, P
Srivastava, SK
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorBauer, Joseph AlanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Centers: Other Centers, Institutes, or Units > Pittsburgh Cancer Institute
Date: 27 August 2012
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 7
Number: 8
DOI or Unique Handle: 10.1371/journal.pone.0043577
Schools and Programs: School of Medicine > Pharmacology and Chemical Biology
Refereed: Yes
Other ID: NLM PMC3428303
PubMed Central ID: PMC3428303
PubMed ID: 22952709
Date Deposited: 18 Oct 2012 20:57
Last Modified: 23 Jan 2019 23:55
URI: http://d-scholarship.pitt.edu/id/eprint/15893

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