2. Academic Validation
  3. MELK expression in ovarian cancer correlates with poor outcome and its inhibition by OTSSP167 abrogates proliferation and viability of ovarian cancer cells

MELK expression in ovarian cancer correlates with poor outcome and its inhibition by OTSSP167 abrogates proliferation and viability of ovarian cancer cells

  • Gynecol Oncol. 2017 Apr;145(1):159-166. doi: 10.1016/j.ygyno.2017.02.016.
Reto S Kohler 1,  Henriette Kettelhack 1,  Alexandra M Knipprath-Mészaros 2,  André Fedier 1,  Andreas Schoetzau 1,  Francis Jacob 3,  Viola Heinzelmann-Schwarz 4
Affiliations

Affiliations

  • 1 Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel, University of Basel, Switzerland.
  • 2 Hospital for Women, Department of Gynecology and Gynecological Oncology, University Hospital Basel, University of Basel, Switzerland.
  • 3 Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel, University of Basel, Switzerland; Glyco-Oncology, Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel, University of Basel, Switzerland. Electronic address: francis.jacob@unibas.ch.
  • 4 Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel, University of Basel, Switzerland; Hospital for Women, Department of Gynecology and Gynecological Oncology, University Hospital Basel, University of Basel, Switzerland. Electronic address: viola.heinzelmann@usb.ch.
PMID: 28214016 DOI: 10.1016/j.ygyno.2017.02.016
Abstract

Objective: Maternal embryonic leucine-zipper kinase (MELK) shows oncogenic properties in basal-like breast Cancer, a Cancer subtype sharing common molecular features with high-grade serous ovarian Cancer. We examined the potential of MELK as a molecular and pharmacological target for treatment of epithelial ovarian Cancer (EOC).

Methods/materials: Bioinformatic analysis was performed on nine OC transcriptomic data sets totaling 1241 patients. Effects of MELK depletion by shRNA or inhibition by OTSSP167 in cell lines were assessed by colony formation and MTT (proliferation) assays, Western blotting (Apoptosis), and flow cytometry (cell cycle analysis).

Results: Elevated MELK expression was correlated with histological grading (n=6 data sets, p<0.05) and progression-free survival (HR 5.73, p<0.01) in OC patients and elevated MELK expression in other cancers with disease-free survival (n=3495, HR 1.071, p<0.001). Inhibition or depletion of MELK reduced cell proliferation and anchorage-dependent and -independent growth in various OC cell lines through a G2/M cell cycle arrest, eventually resulting in Apoptosis. OTSSP167 retained its cytotoxicity in Cisplatin- and Paclitaxel-resistant IGROV1 and TYK-nu OC cells and sensitized OVCAR8 cells to Carboplatin but not Paclitaxel.

Conclusion: MELK inhibition by OTSSP167 may thus present a strategy to treat patients with aggressive, progressive, and recurrent ovarian Cancer.

Keywords

Apoptosis; Disease outcome; Drug resistance; Oncogenic growth; TCGA.

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