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Abstract
The phosphatidylinositol 3-kinase (PI3K) pathway is one of the critical signaling cascades playing important roles in the chemoresistance of human cancer cells, including ovarian cancer. In this study, we investigated the potential of targeting the PI3K p110β-isoform as a novel approach to overcome the chemoresistance in ovarian cancer. The effects on apoptosis, cell viability, proliferation and migration in chemoresistant ovarian cancer cell were determined following targeted p110β inhibition by small interfering RNA (siRNA). Seven paclitaxel (PTX)-resistant sublines (SKpacs and A2780pac) were produced from SKOV3 and A2780 ovarian cancer cell lines. We, first, evaluated the expression of PI3K p110 isoforms in chemosensitive and chemoresistant ovarian cancer cell lines and patient specimens, and found that p110β-isoform was significantly overexpressed both in a panel of ovarian cancer samples, and in PTX-resistant sublines compared with their parent cell lines. RNA interference-mediated p110β silencing augmented PTX-mediated apoptosis (31.15 ± 13.88 %) and reduced cell viability (67 %) in PTX-resistant cells, whereas targeting p110α did not show a significant change in cell viability and apoptosis. In addition, p110β silencing impaired cell proliferation (60 %) in PTX-resistant SKpac cells. We also found the combined treatment group with p110β siRNA and PTX showed a significant inhibition of tumor growth of SKpac cells compared to the PTX-only treated group in a xenograft nude mouse model. Thus, the siRNA-mediated silencing of PI3K p110β resensitizes PTX-resistant ovarian cancer cells, and may be a useful therapeutic strategy for PTX-resistant ovarian cancers.Electronic supplementary materialThe online version of this article (doi:10.1007/s10495-013-0807-9) contains supplementary material, which is available to authorized users.
Highlights
Ovarian carcinoma has the highest mortality rate among the gynecological malignancies
We evaluated the expression of phosphatidylinositol 3-kinase (PI3K) p110 isoforms in human ovarian carcinoma tissue samples and cell lines, and found that b-isoform was significantly overexpressed in ovarian carcinoma tissues and chemoresistant ovarian cancer cell lines
Treatment of parental SKOV3 cell with 80 nM PTX for 48 h resulted in significant induction of apoptosis (98.24 %), whereas a marked reduction in apoptosis was seen in the PTX-resistant SKpac cells (1.1 %) with the same condition of PTX treatment
Summary
Ovarian carcinoma has the highest mortality rate among the gynecological malignancies. The surgical cytoreduction and systemic paclitaxel (PTX)-platinum combination chemotherapy are the choice of treatment. The major reason of the failure of primary treatment is the development of chemoresistance [2]. PTX is an antimicrotubule agent that is currently used as a first-line chemotherapy for the treatment of ovarian, breast, and non-small cell lung. Apoptosis (2013) 18:509–520 cancers [3]. The control of drug-resistance against PTX is one of the important issues in the improved treatment of ovarian cancer. The cause of chemoresistance is multifactorial, and PTX resistance can be mediated by the overexpression of P-glycoprotein and altered expression or post-translational modification of b-tubulin or other microtubule regulatory proteins [4]. The molecular mechanisms of chemoresistance to PTX remain to be investigated
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