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04 September 2019 : Laboratory Research  

Overexpression of Biglycan is Associated with Resistance to Rapamycin in Human WERI-Rb-1 Retinoblastoma Cells by Inducing the Activation of the Phosphatidylinositol 3-Kinases (PI3K)/Akt/Nuclear Factor kappa B (NF-κB) Signaling Pathway

Dong Fang1ABCDEFG, Zhaoguang Lai2BCDE, Yan Wang3AEF*

DOI: 10.12659/MSM.915075

Med Sci Monit 2019; 25:6639-6648

Abstract

BACKGROUND: Biglycan (BGN) is an extracellular matrix (ECM) protein that regulates the growth of epithelial cells. The mammalian target of rapamycin (mTOR) inhibitor, rapamycin, is a treatment for advanced retinoblastoma. This study aimed to investigate the effects of expression of BGN on the response of human WERI-Rb-1 retinoblastoma cells to rapamycin and to investigate the associated signaling pathways.

MATERIAL AND METHODS: BGN gene expression was induced in human WERI-Rb-1 retinoblastoma cells, which were incubated with rapamycin at doses of 0, 5, 10, 20, 30, and 50 μg/ml. Cells were treated with the PI3K/Akt pathway inhibitor, LY294002. The MTT assay determined the rate of cell inhibition. Real-time polymerase chain reaction (RT-PCR) was performed to measure BGN gene expression using RT²-PCR. Western blot detected the protein levels of BGN, p-PI3K, p-Akt, nuclear NF-κB, and p65.

RESULTS: Rapamycin impaired cell growth, induced cell apoptosis, and suppressed the expression levels of p-PI3K, p-Akt, nuclear NF-κB, and p65. Overexpression of the BGN gene restored growth potential and inhibited apoptosis and was associated with the activation of the PI3K/Akt-mediated NF-κB pathway. In cells that overexpressed BGN, inhibition of the PI3K/Akt pathway by LY294002 increased the sensitivity of human WERI-Rb-1 retinoblastoma cells to rapamycin.

CONCLUSIONS: Overexpression of BGN induced rapamycin resistance in WERI-Rb-1 retinoblastoma cells by activating PI3K/Akt/NF-κB signaling.

Keywords: Biglycan, Drug Resistance, Neoplasm, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Retinoblastoma, Apoptosis, Cell Proliferation, Gene Expression Regulation, Neoplastic, Inhibitory Concentration 50, NF-kappa B, Signal Transduction, Sirolimus

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750