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.

Phenethyl isothiocyanate suppresses the metastasis of ovarian cancer associated with the inhibition of CRM1-mediated nuclear export and mTOR-STAT3 pathway

“…Previous studies have elucidated possible molecular mechanisms, including apoptosis induction and proliferation inhibition. 31,32 In the current study, we verified that PEITC inhibited the migration and invasion of EOC in vitro and in vivo. We also explored the possible mechanisms of PEITC in EOC cell lines.…”

Mechanisms of the Anticancer Effects of Isothiocyanates

“…In our study, we have demonstrated that PEITC inhibits EGFR and HER2 in ovarian and breast cancer with significant inhibition of activated EGFR (Tyr1068) [55,62,63]. In other studies, PEITC has been shown to inhibit phosphorylation of Akt and mTOR [62].…”

“…Also, PEITC has been found to cross blood-brain barrier as well which makes it a candidate with antimetastatic potential to the brain. Oral administration of PEITC was demonstrated by many studies to inhibit oncogenic pathways like EGFR, HER2, and Akt in vivo [54,55,62]. Furthermore, looking at the side effect, it was shown by a study that intraperitonial (i.p.)…”

PEITC treatment suppresses myeloid derived tumor suppressor cells to inhibit breast tumor growth

“…A plethora of pre-clinical studies suggest a strong anticancer activity of PEITC. [15][16][17][18][19][20][21][22][23][24] Phase I and II clinical trials are also in progress to test PEITC against lung cancer and leukemia. 25 Hence we evaluated the effects of PEITC on tumor-modulatory immune cells circulating in the blood.…”