Abstract
Epithelial ovarian carcinoma (EOC) is the most lethal gynecological malignancy. Herein, we sought to determine the efficacy of phosphoinositide 3-kinase (PI3K)/Akt inhibition using three AZD compounds in a NOD-SCID xenograft mouse model and Akt regulation in a panel of eight ovarian cancer cell lines. Elevated Akt phosphorylation on Ser473 but not on Thr308 in cancerous tissues correlated with short progression-free survival (PFS), overall survival (OS), and death. AZD8835 and AZD8186 inhibited Akt phosphorylation while AZD5363 augmented its phosphorylation on Ser473. To add, all compounds inhibited the Akt downstream effectors 4E-BP1 and p70S6 kinase. AZD8835 and AZD5363 sensitized chemoresistant ovarian cancer cells to cisplatin and paclitaxel treatment. Only AZD5363 could inhibit COL11A1 mRNA and promoter activity, which are important factors in Akt regulation and chemoresistance in ovarian cancer. By using a mouse xenograft model, AZD8835 and AZD5363, but not AZD8186, caused a significant reduction in tumor formation. AZD compounds did not change the mRNA expression of BRCA1/BRCA in ovarian cancer cells, but AZD8835 inhibited BRCA1/BRCA2 mRNA expression and p-ERK protein expression in OVCAR-8 cells with the KRAS mutation. This study highlights the importance of PI3K/Akt in ovarian tumor progression and chemoresistance and the potential application of AZD compounds, especially AZD8835 and AZD5363, as therapeutic agents for the treatment of ovarian cancer.
Highlights
Epithelial ovarian carcinoma (EOC) is the most lethal gynecological malignancy (Siegel et al, 2012)
Survival analyses of 406 ovarian cancer patients obtained from the the Cancer Proteome Atlas (TCPA) database showed that the protein expression of p-Akt (S473; Figure 1A) but not p-Akt (T308; Figure 1B) correlated with overall survival (OS) of these patients
Akt phosphorylation on Ser473 has been extensively studied in tumor samples as a biomarker for Akt activity and clinical outcome, but only limited studies have assessed its effect on Thr308
Summary
Epithelial ovarian carcinoma (EOC) is the most lethal gynecological malignancy (Siegel et al, 2012). The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) is a critical regulator of many cellular processes, including metabolism, growth, and anti-apoptosis, and is frequently dysregulated in human cancers (Thorpe et al, 2015). Class I PI3Ks are further divided into subclasses IA and IB, and IA subclass is the most frequently activated in cancer (Thorpe et al, 2015). Multiple mechanisms may be involved in PI3K mutation and aberrant activation in human cancers (Samuels and Ericson, 2006; Engelman, 2009; Jaiswal et al, 2009; Vanhaesebroeck et al, 2010; Cheung et al, 2011; Cancer Genome Atlas Research Network, 2012; Walter et al, 2018). Akt activation involves the phosphorylation of two residues: threonine 308 (T308) in the activation loop of the kinase by the protein kinase, Akt-3-phosphoinositide-dependent kinase 1 (PDK1), and serine 473 (S473) in the hydrophobic motif of the mTORC2 complex (Alessi et al, 1997; Vanhaesebroeck and Alessi, 2000; Sarbassov et al, 2005)
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