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WEE1 inhibition by MK1775 as a single-agent therapy inhibits ovarian cancer viability.

ABSTRACT: Wee1-like protein kinase (WEE1) physiologically serves a key function in maintaining the integrity of the cell genome through mediating the activation of cyclin-dependent kinase (CDK)1 and CDK2. Increased expression of WEE1 has been associated with the poor prognosis of patients with ovarian cancer. The present study aimed at examining the in vitro and in vivo antitumor activity of MK1775, a potent pharmacological inhibitor of WEE1, as a single agent against ovarian cancer cells. The cytotoxicity of MK1775 was examined in a panel of tumor cells using MTT in vitro. Subsequently, a cell apoptosis assay was performed in ovarian cancer SKOV3 and ID8 cells to characterize the function of MK1775 in tumor cell apoptosis, under either wild-type tumor protein 53 (p53) or null p53 status. In addition, cell cycle analysis and a western blot analysis were performed to validate the effect of MK1775 on cell cycle progression and to elucidate the underlying molecular mechanism of cell death. Finally, the in vivo antitumor efficacy of MK1775 as a single agent at a clinical well-tolerated dose was determined. A dose-dependent inhibitory effect of MK1775 on tumor cell viability was determined in distinct cell lines, including B16F10, LLC1, BPS1, EG7, ID8 and SKOV3. Results from the cell cycle analysis and western blotting indicated that MK1775 abrogated the G2/M checkpoint through inhibiting the phosphorylation of CDK1 and inducing the apoptosis of ovarian cancer cells that lacked mutations in p53 and breast cancer 1 (BRCA1). Additionally, a significant antitumor effect of MK1775 was observed in C57BL/6 mice bearing syngeneic ID8 ovarian tumors. The results of the present study supported the use of MK1775 as a monotherapy agent in ovarian cancer. MK1775 was effective at inducing mitotic catastrophe, independent of p53 and BRCA1 mutations. Therefore, WEE1 inhibition by MK1775 requires additional investigation to identify novel combination approaches in ovarian cancer therapy with the current DNA damaging agents, including irradiation treatment and cell cycle checkpoint inhibitors.

SUBMITTER: Zhang M

PROVIDER: S-EPMC5588002 | biostudies-other | 2017 Sep

REPOSITORIES: biostudies-other

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WEE1 inhibition by MK1775 as a single-agent therapy inhibits ovarian cancer viability.

Zhang Minghui M Dominguez Donye D Chen Siqi S Fan Jie J Qin Lei L Long Alan A Li Xia X Zhang Yi Y Shi Huirong H Zhang Bin B

Oncology letters 20170715 3

Wee1-like protein kinase (WEE1) contributes to the upstream regulation of the cyclin-dependent kinase (CDK) complexes by mediating the inactivation of CDK1 [corrected]. Increased expression of WEE1 has been associated with the poor prognosis of patients with ovarian cancer. The present study aimed at examining the <i>in vitro</i> and <i>in vivo</i> antitumor activity of MK1775, a potent pharmacological inhibitor of WEE1, as a single agent against ovarian cancer cells. The cytotoxicity of MK1775 ...[more]

PMID: 28927115

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Project description:Osteopontin (OPN) is upregulated in several types of tumor and has been associated with chemoresistance. However, the contribution of OPN splicing isoforms (OPN‑SIs) to chemoresistance requires further investigation. The present study aimed to evaluate the expression patterns of each tested OPN‑SI in cisplatin (CDDP)‑resistant ovarian carcinoma cell lines, focusing on the role of the OPN‑c isoform (OPNc) in drug resistance. ACRP ovarian cancer cells resistant to CDDP, as well as their parental cell line A2780, were used. Analyses of the transcriptional expression of OPN‑SIs, epithelial‑mesenchymal transition (EMT) markers and EMT‑related cytokines were performed using reverse transcription‑quantitative PCR. OPNc was silenced in ACRP cells using anti‑OPNc DNA oligomers and stably overexpressed by transfecting A2780 cells with a mammalian expression vector containing the full length OPNc cDNA. Functional assays were performed to determine cell proliferation, viability and colony formation. The results demonstrated that among the three tested OPN‑SIs, OPNc was the most upregulated transcript in the ACRP cells compared with the parental A2780 cells. In addition, the expression levels of P‑glycoprotein multidrug transporter were upregulated in CDDP‑resistant ACRP cells compared with those in A2780 cells. OPNc knockdown sensitized ACRP cells to CDDP treatment and downregulated P‑gp expression levels compared with those in the negative control group. Additionally, silencing of OPNc impaired cell proliferative and colony formation abilities, as well as reversed the expression levels of EMT markers and EMT‑related cytokines compared with those in the negative control cells. Notably, although stable OPNc overexpression resulted in increased A2780 cell proliferation, it notably increased CDDP sensitivity compared with that in the cells transfected with a control vector. These results suggested that OPNc silencing may represent a putative approach to sensitize resistant ovarian cancer cells to chemotherapeutic agents.

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WEE1 inhibition by MK1775 as a single-agent therapy inhibits ovarian cancer viability.

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WEE1 inhibition by MK1775 as a single-agent therapy inhibits ovarian cancer viability.

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