Phosphatidylinositol 3′-Kinase Activation Leads to Multidrug Resistance Protein-1 Expression and Subsequent Chemoresistance in Advanced Prostate Cancer Cells

Abstract

The development of androgen-independent growth in advanced carcinoma of the prostate (CaP) is associated with poor prognosis and few therapeutic options. Chemotherapeutic drugs offer the afflicted patient palliative benefits, but these are short-lived because of the chemoresistant nature of hormone-refractory prostate cancer. Given the high percentage of CaP patients with mutations in the PTEN tumor suppressor gene, we sought to determine the involvement of the phosphatidylinositol 3-kinase (PI3K) cascade in the development of CaP drug resistance. PTENnegative PC3 cells were observed to have increased resistance to both doxorubicin and paclitaxel when compared with PTEN-positive DU145 cells. Furthermore, modulation of PI3K activity with the use of constitutively active and dominant-negative inhibitors was found to affect the ability to CaP cells to respond to chemotoxic treatments. Additionally, inhibition of PI3K with a small molecular weight inhibitor (LY294002) was able to potentiate the antineoplastic activity of both doxorubicin and paclitaxel in CaP cells. Interestingly, multidrug resistance protein-1 (MRP-1) expression, but not MDR-1 (p-glycoprotein), was observed to be induced as a consequence of PI3K activation in these cell types. Inhibition of MRP-1 expression via siRNA was observed to synergistically sensitize CaP cells to chemotoxic drugs while having no appreciable effect on cell growth in the absence of these compounds. Taken together, these data suggest that PI3K activation can lead to the development of chemoresistant cells in prostatic carcinomas through the up-regulation of MRP-1. Thus, inhibition of PI3K activity with concomitant administration of chemotoxic compounds may prove beneficial in preventing the development of drug resistance in patients with hormone-refractory prostate cancer.

Cyclooxygenase-independent down-regulation of multidrug resistance–associated protein-1 expression by celecoxib in human lung cancer cells

“…Recently, phosphatidylinositol 3V -kinase was shown to modulate MRP1 gene expression in prostate cancer cells, leading to chemoresistance (18). Celecoxib, at concentrations similar to those used in our study, has been found to induce the inactivation of Akt, a major downstream molecule of the phosphatidylinositol 3V -kinase pathway, in a wide range of cancer cells (19).…”

The PI3K inhibitor LY294002 blocks drug export from resistant colon carcinoma cells overexpressing MRP1

“…In advanced prostate carcinoma, the PI3K pathway controls chemoresistance to doxorubicin and paclitaxel through upregulation of multidrug resistance protein 1 (MRP1) at the RNA and protein level. Silencing of MRP1 expression by RNA interference rendered cultured prostate cancer cells susceptible to these drugs (Lee et al, 2004). The MRP1 protein is differentially expressed in HT29RDB cells, however, LY294002 treatment did not upregulate MRP1 levels, therefore, we excluded the possibility that LY294002 exerts its effects by affecting the drug transporter MRP1 expression in HT29RDB cells.…”

“…Most importantly for the issue of therapy, enhanced sensitivity to drug treatment was observed in the presence of signalling inhibitors. PI3K inhibition was particularly effective sensitizing pancreatic adenocarcinoma cells (Ng et al, 2000), ovarian cancer cell lines (Ding et al, 2001;Hu et al, 2002), breast cancer cells (Clark et al, 2002;Jin et al, 2003), hormone-refractory prostate cancer cells (Lee et al, 2004), metastatic colon cancer cells (Wang et al, 2002) and lung cancer cells (Nakashio et al, 2000;Brognard et al, 2001). Similar effects have been reported for MAPK inhibition (Ding et al, 2001;Jin et al, 2003).…”

RAD001 (Everolimus) inhibits growth of prostate cancer in the bone and the inhibitory effects are increased by combination with docetaxel and zoledronic acid

“…mTOR, originally identified as the mammalian target of rapamycin, is a serine/threonine kinase that plays a central role in control of translation and also regulates anti-apoptotic signals (reviewed in Castedo et al [11]). The potential clinical utility of inhibition of the mTOR pathway in CaP is supported by published reports of inhibition of CaP growth by rapamycin and its derivatives [12][13][14][15][16][17]. RAD001 (Everolimus), an orally bioavailable mTOR inhibitor, induces apoptosis of epithelial cells and completely reverses the neoplastic phenotype of mice expressing human AKT1 in the prostate [18].…”