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 s… Show more
“…Similar to the previous findings in PC3 and DU145 prostate cancer cells 16 , docetaxel did not decrease the levels of P70S6K phosphorylation (a marker for mTOR activity), SK1 mRNA or activity, but rather insignificantly increased them (Fig. 2).…”
Section: Resultssupporting
confidence: 90%
“…In MDA-MB-231 breast cancer cells p-P70S6K ELISA findings were confirmed using Western blotting (Figure S2). In PC3 and DU145 prostate cancer cells, we have previously shown that Western blotting and ELISA show similar results 16 .Figure 2RAD001 but not docetaxel decreases SK1 expression in MDA-MB-231 and PC3 cells. MDA-MB-231 and PC3 cells were starved overnight then incubated with 0.1% DMSO (Cont), 100 nM RAD001 (RAD), 5 nM docetaxel (Doc) and the combination of these drugs (RAD + Doc) for 24 h. ( A , D ) P70S6K phosphorylation was measured using ELISA.…”
Resistance to docetaxel is a key problem in current prostate and breast cancer management. We have recently discovered a new molecular mechanism of prostate cancer docetaxel chemoresistance mediated by the mammalian target of rapamycin (mTOR)/sphingosine-kinase-1 (SK1) pathway. Here we investigated the influence of this pathway on vascular endothelial growth factor (VEGF) production and tumour vascularisation in hormone resistant prostate and breast cancer models. Immunofluorescent staining of tumour sections from human oestrogen receptor (ER)-negative breast cancer patients showed a strong correlation between phosphorylated P70S6 kinase (mTOR downstream target), VEGF and SK1 protein expression. In hormone-insensitive prostate (PC3) and breast (MDA-MB-231 and BT-549) cancer cell lines the mTOR inhibitor RAD001 (everolimus) has significantly inhibited SK1 and VEGF expression, while low dose (5 nM) docetaxel had no significant effect. In these cell lines, SK1 overexpression slightly increased the basal levels of VEGF, but did not block the inhibitory effect of RAD001 on VEGF. In a human prostate xenograft model established in nude mice, RAD001 alone or in combination with docetaxel has suppressed tumour growth, VEGF expression and decreased tumour vasculature. Overall, our data demonstrate a new mechanism of an independent regulation of SK1 and VEGF by mTOR in hormone-insensitive prostate and breast cancers.
“…Similar to the previous findings in PC3 and DU145 prostate cancer cells 16 , docetaxel did not decrease the levels of P70S6K phosphorylation (a marker for mTOR activity), SK1 mRNA or activity, but rather insignificantly increased them (Fig. 2).…”
Section: Resultssupporting
confidence: 90%
“…In MDA-MB-231 breast cancer cells p-P70S6K ELISA findings were confirmed using Western blotting (Figure S2). In PC3 and DU145 prostate cancer cells, we have previously shown that Western blotting and ELISA show similar results 16 .Figure 2RAD001 but not docetaxel decreases SK1 expression in MDA-MB-231 and PC3 cells. MDA-MB-231 and PC3 cells were starved overnight then incubated with 0.1% DMSO (Cont), 100 nM RAD001 (RAD), 5 nM docetaxel (Doc) and the combination of these drugs (RAD + Doc) for 24 h. ( A , D ) P70S6K phosphorylation was measured using ELISA.…”
Resistance to docetaxel is a key problem in current prostate and breast cancer management. We have recently discovered a new molecular mechanism of prostate cancer docetaxel chemoresistance mediated by the mammalian target of rapamycin (mTOR)/sphingosine-kinase-1 (SK1) pathway. Here we investigated the influence of this pathway on vascular endothelial growth factor (VEGF) production and tumour vascularisation in hormone resistant prostate and breast cancer models. Immunofluorescent staining of tumour sections from human oestrogen receptor (ER)-negative breast cancer patients showed a strong correlation between phosphorylated P70S6 kinase (mTOR downstream target), VEGF and SK1 protein expression. In hormone-insensitive prostate (PC3) and breast (MDA-MB-231 and BT-549) cancer cell lines the mTOR inhibitor RAD001 (everolimus) has significantly inhibited SK1 and VEGF expression, while low dose (5 nM) docetaxel had no significant effect. In these cell lines, SK1 overexpression slightly increased the basal levels of VEGF, but did not block the inhibitory effect of RAD001 on VEGF. In a human prostate xenograft model established in nude mice, RAD001 alone or in combination with docetaxel has suppressed tumour growth, VEGF expression and decreased tumour vasculature. Overall, our data demonstrate a new mechanism of an independent regulation of SK1 and VEGF by mTOR in hormone-insensitive prostate and breast cancers.
“…Recent studies showed that inflammatory cytokines, including IL6, and transcription factors STAT3 and NF-κB, play critical roles in cancer drug resistance (46, 59). S1P is also known to play a role in drug resistance in various types of cancer (60–65). We found that NF-κB levels are predictive of doxorubicin response utilizing doxorubicin treated patients sample data.…”
Background
Doxorubicin is one of the most commonly used chemotherapeutic drugs for breast cancer; however, its use is limited by drug resistance and side-effects. We hypothesized that adding FTY720, a sphingosine-1- phosphate (S1P) receptor functional antagonist, to doxorubicin would potentiate its effects by suppression of drug-induced inflammation.
Materials and Methods
The Cancer Genome Atlas (TCGA), GEO datasets, and NCI-60 panel were used for gene expressions and gene set enrichment analysis (GSEA). E0771 syngeneic mammary tumor cells were used. OB/OB mice fed with western high fat diet were used as an obesity model.
Results
STAT3 expression was significantly increased after doxorubicin treatment in human breast cancer that implicates that doxorubicin evokes inflammation. Expression of sphingosine kinase 1 (SphK1), the enzyme that produces S1P and links inflammation and cancer, tended to be higher in doxorubicin resistant human cancer and cell lines. In a murine breast cancer model, SphK1, S1P receptor 1 (S1PR1), IL6 and STAT3 were over-expressed in the doxorubicin treated group, whereas all of them were significantly suppressed with addition of FTY720. Combination therapy synergistically suppressed cancer growth both in vitro and in vivo. Furthermore, combination therapy showed higher efficacy in an obesity breast cancer model, where high body mass index (BMI) demonstrated trends toward worse disease free and overall survival, and high serum S1P levels in human patients and volunteers.
Conclusions
We found that FTY720 enhanced the efficacy of doxorubicin by suppression of drug-induced inflammation, and combination therapy showed stronger effect in obesity-related breast cancer.
“…Additionally, prolonged SK1 inhibition generates a wide genetic response, including upregulation of multiple prosurvival pathways as well as expression of SK2, which provides cells with missing S1P (149). This again warrants a trial evaluating the use of SK1 inhibitors in combination with other molecular therapy or chemotherapy (122,150), or alternatively one utilizing pan-SK inhibitors, rather than selective SK1 inhibitors. 4) Use of nanocarriers in delivering combination therapies.…”
Section: Conclusion and Future Perspectivesmentioning
It is now well-established that sphingosine kinase 1 (SK1) plays a significant role in breast cancer development, progression, and spread, whereas SK1 knockdown can reverse these processes. In breast cancer cells and tumors, SK1 was shown to interact with various pathways involved in cell survival and chemoresistance, such as nuclear factor-kappa B (NFκB), Notch, Ras/MAPK, PKC, and PI3K. SK1 is upregulated by estrogen signaling, which, in turn, confers cancer cells with resistance to tamoxifen. Sphingosine-1-phosphate (S1P) produced by SK1 has been linked to tumor invasion and metastasis. Both SK1 and S1P are closely linked to inflammation and adipokine signaling in breast cancer. In human tumors, high SK1 expression has been linked with poorer survival and prognosis. SK1 is upregulated in triple negative tumors and basal-like subtypes. It is often associated with high phosphorylation levels of ERK1/2, SFK, LYN, AKT, and NFκB. Higher tumor SK1 mRNA levels were correlated with poor response to chemotherapy. This review summarizes the up-to-date evidence and discusses the therapeutic potential for the SK1 inhibition in breast cancer, with emphasis on the mechanisms of chemoresistance and combination with other therapies such as gefitinib or docetaxel. We have outlined four key areas for future development, including tumor microenvironment, combination therapies, and nanomedicine. We conclude that SK1 may have a potential as a target for precision medicine, its high expression being a negative prognostic marker in ER-negative breast cancer, as well as a target for chemosensitization therapy.
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