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Abstract
Sulforaphane exerts anti-cancer activity against multiple cancer types. Our objective was to evaluate utility of sulforaphane for endometrial cancer therapy. Sulforaphane reduced viability of endometrial cancer cell lines in association with the G2/M cell cycle arrest and cell division cycle protein 2 (Cdc2) phosphorylation, and intrinsic apoptosis. Inhibition of anchorage-independent growth, invasion, and migration of the cell lines was associated with sulforaphane-induced alterations in epithelial-to-mesenchymal transition (EMT) markers of increased E-cadherin and decreased N-cadherin and vimentin expression. Proteomic analysis identified alterations in AKT, mTOR, and ERK kinases in the networks of sulforaphane effects in the Ishikawa endometrial cancer cell line. Western blots confirmed sulforaphane inhibition of AKT, mTOR, and induction of ERK with alterations in downstream signaling. AKT and mTOR inhibitors reduced endometrial cancer cell line viability and prevented further reduction by sulforaphane. Accumulation of nuclear phosphorylated ERK was associated with reduced sensitivity to the ERK inhibitor and its interference with sulforaphane activity. Sulforaphane induced apoptosis-associated growth inhibition of Ishikawa xenograft tumors to a greater extent than paclitaxel, with no evidence of toxicity. These results verify sulforaphane’s potential as a non-toxic treatment candidate for endometrial cancer and identify AKT, mTOR, and ERK kinases in the mechanism of action with interference in the mechanism by nuclear phosphorylated ERK.
Highlights
Over the past few decades, the incidence and mortality of endometrial cancer have increased, and the age of onset has decreased due to the global increase in the prevalence of obesity in younger women [1,2]
To examine the potential utility of incorporating sulforaphane (Figure 1A) treatment in the care of endometrial cancer patients, we first measured its cytotoxicity against cell lines established from human endometrial cancers possessing a range of cellular differentiation statuses
Since sulforaphane demonstrated reduction of cell invasion cell invasion and metastases, we evaluated the expression of Epithelial to mesenchymal transition (EMT)-related markers in endometrial and metastases, we evaluated the expression of EMT-related markers in endometrial cells treated cells with sulforaphane
Summary
Over the past few decades, the incidence and mortality of endometrial cancer have increased, and the age of onset has decreased due to the global increase in the prevalence of obesity in younger women [1,2]. Patients with early-stage endometrial cancer are efficaciously treated with surgery, with or without chemo-radiotherapy, resulting in five-year survival rates of 80–85% [4], these therapeutic options are limited in younger patients due to the desire to preserve fertility and in obese patients due to poor hormonal sensitivity and surgical outcomes and higher cost of surgical care [5]. Twenty percent to 30% of endometrial cancer patients are diagnosed with the late-stage disease. Cancers 2020, 12, 1273 at the time of surgery, with an estimated five-year survival rate of 40–70% for stage III patients, and a very poor five-year survival of 0–10% for stage IV patients [6]. The current standard of care for patients with advanced or recurrent endometrial cancer is systemic treatment with carboplatin and paclitaxel. A large phase III non-inferiority study performed by the Gynecologic Oncology
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