Abstract
Resistance to docetaxel is a key problem in current prostate cancer management. Sphingosine kinase 1 (SK1) and phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathways have been implicated in prostate cancer chemoresistance. Here we investigated whether their combined targeting may re-sensitize prostate cancer cells to docetaxel.In hormone-insensitive PC-3 and DU145 prostate cancer cells the mTOR inhibitor everolimus (RAD001) alone did not lead to significant cell death, however, it strongly sensitized cells to low levels (5 nM) of docetaxel. We show that mTOR inhibition has led to a decrease in hypoxia-inducible factor-1α (HIF-1α) protein levels and SK1 mRNA. HIF-1α accumulation induced by CoCl2 has led to a partial chemoresistance to RAD001/docetaxel combination. SK1 overexpression has completely protected prostate cancer cells from RAD001/docetaxel effects. Using gene knockdown and CoCl2 treatment we showed that SK1 mRNA expression is downstream of HIF-1α. In a human xenograft model in nude mice single RAD001 and docetaxel therapies induced 23% and 15% reduction in prostate tumor volume, respectively, while their combination led to a 58% reduction. RAD001 alone or in combination with docetaxel has suppressed intratumoral mTOR and SK1 signaling, however as evidenced by tumor size, it required docetaxel for clinical efficacy. Combination therapy was well tolerated and had similar levels of toxicity to docetaxel alone.Overall, our data demonstrate a new mechanism of docetaxel sensitization in prostate cancer. This provides a mechanistic basis for further clinical application of RAD001/docetaxel combination in prostate cancer therapy.
Highlights
Prostate cancer is the most frequently diagnosed cancer among men in developed countries and the second most common cause of cancer related mortality [1]
Our findings suggest that RAD001 is a potent sensitizer to low doses of docetaxel in prostate cancer cell culture models
We have previously shown that Sphingosine kinase 1 (SK1) mediates prostate cancer docetaxel chemoresistance [20] and we have shown that cytotoxic concentrations of docetaxel (20 nM) inhibit SK1 in prostate cancer cells, while lower, less effective concentrations of docetaxel (5 nM) do not have such effect
Summary
Prostate cancer is the most frequently diagnosed cancer among men in developed countries and the second most common cause of cancer related mortality [1]. Androgen suppression is the principal initial systemic therapy for metastatic prostate cancer [2]. Inherent or acquired resistance to androgen therapy remains a major clinical obstacle [3] and eventually most patients with advanced disease relapse [4]. Docetaxel chemotherapy offered to these patients only extends survival for a median period of less than 3 months [5]. It was found that in men with hormone-sensitive metastatic prostate cancer early docetaxel administration combined with www.impactjournals.com/oncotarget androgen deprivation therapy statistically significantly improved overall survival by 10 months, compared with androgen deprivation therapy alone [7]. Considering that docetaxel effect on the median overall survival in metastatic castration-resistant prostate cancer (mCRPC) is several-fold less than its impact in hormone-sensitive metastatic prostate cancer, it is imperative to identify potential chemotherapy targets that might sensitize mCRPC cells to taxane therapies
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