Up-regulation of insulin-like growth factor-binding protein 3 by 5-fluorouracil (5-FU) leads to the potent anti-proliferative effect of androgen deprivation therapy combined with 5-FU in human prostate cancer cell lines

Kawabata, Rumi; Oie, Shinji; Takahashi, Masayuki; Kanayama, Hiro‐omi; Oka, Toshinori; Itoh, Kohji

doi:10.3892/ijo.2011.991

Cited by 11 publications

(9 citation statements)

References 36 publications

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“…Bicalutamide was found to inhibit androgen-independent prostate cancer cell growth appeared through AR-independent pathways [ 45 , 46 ]. One study showed that combination of bicalutamide with other therapeutic agents enhanced the CRPC growth inhibition via up-regulation of insulin-like growth factor-binding protein 3 (IGFBP3) [ 47 ]. Also, previous study indicated that MUC1-C subunit suppressed AR expression through a posttranscriptional mechanism and resisted to bicalutamide treatment in androgen-dependent prostate cancer cells, this implied that inhibition of AR expression by MUC1-C led to develop more aggressive androgen-independent phenotype in prostate cancer cells that was sensitive to MUC1-C inhibition [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

Combination of curcumin and bicalutamide enhanced the growth inhibition of androgen-independent prostate cancer cells through SAPK/JNK and MEK/ERK1/2-mediated targeting NF-κB/p65 and MUC1-C

Xiang

Zhang

et al. 2015

J Exp Clin Cancer Res

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BackgroundProstate cancer is one of the most common malignancies in men. The mucin 1 (MUC1) heterodimeric oncoprotein is overexpressed in human prostate cancers with aggressive pathologic and clinical features, resulting in a poor outcome. However, the functional role for MUC1 C-terminal domain (MUC1-C) in androgen-independent prostate cancer occurrence and development has remained unclear.MethodsCell viability was measured by MTT assays. Western blot analysis was performed to measure the phosphorylation and protein expression of SAPK/JNK and ERK1/2, and MUC1-C, NF-κB subunit p65 and p50. Exogenous expression of MUC1-C, NF-κB subunit p65 was carried out by transient and electroporated transfection assays.ResultsWe showed that curcumin inhibited the growth of androgen-independent prostate cancer cells and a synergy was observed in the presence of curcumin and bicalutamide, the androgen receptor antagonist. To further explore the potential mechanism underlining this, we found that curcumin increased the phosphorylation of ERK1/2 and SAPK/JNK, which was enhanced by bicalutamide. In addition, curcumin reduced the protein expression of MUC1-C and NF-κB subunit p65, which were abrogated in the presence of the inhibitors of MEK/ERK1/2 (PD98059) and SAPK/JNK (SP60015). A further reduction was observed in the combination of curcumin with bicalutamide. Moreover, while exogenous expression of MUC1-C had little effect on curcumin-reduced p65, the overexpression of p65 reversed the effect of curcumin on MUC1-C protein expression suggesting that p65 is upstream of MUC1-C. Intriguingly, we showed that exogenous expression of MUC1-C feedback diminished the effect of curcumin on phosphorylation of ERK1/2 and SAPK/JNK, and antagonized the effect of curcumin on cell growth.ConclusionOur results show that curcumin inhibits the growth of androgen-independent prostate cancer cells through ERK1/2- and SAPK/JNK-mediated inhibition of p65, followed by reducing expression of MUC1-C protein. More importantly, there are synergistic effects of curcumin and bicalutamide. The negative feedback regulatory loop of MUC1-C to ERK1/2 and SAPK/JNK further demonstrates the role of MUC1-C that contributes to the overall responses of curcumin. This study unveils the potential molecular mechanism by which combination of curcumin with bicalutamide enhances the growth inhibition of androgen-independent prostate cancer cells.

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Section: Discussionmentioning

confidence: 99%

Combination of curcumin and bicalutamide enhanced the growth inhibition of androgen-independent prostate cancer cells through SAPK/JNK and MEK/ERK1/2-mediated targeting NF-κB/p65 and MUC1-C

Xiang

Zhang

et al. 2015

J Exp Clin Cancer Res

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“…A recent study demonstrated that, in breast cancer, trastuzumab regulates IGFBP-2 and -3 expression, which impacts IGF1R downstream signaling (35). Cytotoxic agents can also regulate IGFBP secretion: increased secretion of IGFBP-3 in prostate cancer cells treated with 5-fluorouracil plays an important role in its pro-apoptotic effect (36). Thus, due to the complexities of the IGF system and its regulation, further investigation will be required to identify a reliable marker of IGF1R-based resistance to therapy.…”

Section: Discussionmentioning

confidence: 99%

Activation of the Insulin-like Growth Factor-1 Receptor Induces Resistance to Epidermal Growth Factor Receptor Antagonism in Head and Neck Squamous Carcinoma Cells

Jameson

Beckler

Taniguchi

et al. 2011

Molecular Cancer Therapeutics

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Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have poor efficacy in head and neck squamous cell carcinoma (HNSCC). Because the insulin-like growth factor-1 receptor (IGF1R) generates potent prosurvival signals and has been implicated in therapeutic resistance, its ability to induce resistance to EGFR-TKIs was studied in vitro. Five HNSCC cell lines demonstrated reduced sensitivity to the EGFR-TKI gefitinib when the IGF1R was activated. In SCC-25 and Cal27 cells, gefitinib inhibited basal and EGF-stimulated EGFR, Erk and Akt phosphorylation and reduced cell number. This correlated with initiation of apoptosis based on a 4-fold increase poly-(ADP-ribose) polymerase (PARP) cleavage and a 2.5-fold increase in Annexin V positivity. The apoptotic response and reduction in cell number were blocked by IGF1R activation, which resulted in phosphorylation of both Erk and Akt. In both cell lines, IGF1R-induced Erk but not Akt activation was eliminated by gefitinib. IGF1R-induced gefitinib resistance was unaffected by MEK inhibition with U0126, but was partially impaired by inhibition of phosphatidylinositol 3′-kinase (PI3K) with LY294002. The IGF1R-TKI PQ401 inhibited growth of SCC-25 and Cal27 cells alone and also acted synergistically with gefitinib. Thus the IGF1R can make HNSCC cells resistant to EGFR-TKI treatment via a prosurvival mechanism. Of 8 studied, all HNSCC tumor samples expressed the IGF1R and 5 demonstrated detectable IGF1R phosphorylation, suggesting that this receptor may be relevant in vivo, and thus combined EGFR/IGF1R inhibition may be necessary in some patients for effective targeted molecular therapy.

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“…Activation of the tumor suppressor p53 in response to chemotherapy or radiotherapy plays an important part in the cytotoxic effects of these therapies [ 67 ]. Since the discovery of IGFBP3 as a p53-inducible gene in 1995 [ 68 ], studies in many cancer cell lines have demonstrated an increase in the expression of IGFBP-3 in response to treatment by chemotherapeutic drugs [ 69 – 71 ]. Because exogenous IGFBP-3 has proapoptotic activity in many cell types, including breast cancer cells, either when used alone [ 72 ] or in combination with other apoptotic agents such as C 2 ceramide [ 73 ], chemotherapy drugs [ 70 ], or radiation [ 19 ], the induction of IGFBP-3 in response to DNA-damaging therapies has been assumed to contribute to the cytotoxicity of these treatments.…”

Section: Igfbp-3 and The Dna Damage Response: Can Igfbp-3 Alter Rementioning

confidence: 99%

Targeting Insulin-Like Growth Factor Binding Protein-3 Signaling in Triple-Negative Breast Cancer

Marzec

Baxter

Martin

2015

BioMed Research International

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Insulin-like growth factor binding protein-3 (IGFBP-3) is a key regulatory molecule of the IGF axis and can function in a tissue-specific way as both a tumor suppressor and promoter. Triple-negative breast cancer (TNBC) has high tumor expression of IGFBP-3 associated with markers of poor prognosis and, although accounting for 15–20% of all breast cancers, is responsible for disproportionate rates of morbidity and mortality. Because they lack estrogen and progesterone receptors and overexpression of HER2, TNBC are resistant to treatments that target these molecules, making the development of new therapies an important goal. In addition to frequent high expression of IGFBP-3, these tumors also express EGFR highly, but targeting EGFR signaling alone in TNBC has been of little success. Identification of a functional growth-stimulatory interaction between EGFR and IGFBP-3 signaling prompted investigation into cotargeting these pathways as a novel therapy for TNBC. This involves inhibition of both EGFR kinase activity and a mediator of IGFBP-3's stimulatory bioactivity, sphingosine kinase-1 (SphK1), and has shown promise in a preclinical setting. Functional interaction between EGFR and IGFBP-3 may also promote chemoresistance in TNBC, and delineating the mechanisms involved may identify additional targets for development of therapies in cancers that express both IGFBP-3 and EGFR.

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Up-regulation of insulin-like growth factor-binding protein 3 by 5-fluorouracil (5-FU) leads to the potent anti-proliferative effect of androgen deprivation therapy combined with 5-FU in human prostate cancer cell lines

Cited by 11 publications

References 36 publications

Combination of curcumin and bicalutamide enhanced the growth inhibition of androgen-independent prostate cancer cells through SAPK/JNK and MEK/ERK1/2-mediated targeting NF-κB/p65 and MUC1-C

Combination of curcumin and bicalutamide enhanced the growth inhibition of androgen-independent prostate cancer cells through SAPK/JNK and MEK/ERK1/2-mediated targeting NF-κB/p65 and MUC1-C

Activation of the Insulin-like Growth Factor-1 Receptor Induces Resistance to Epidermal Growth Factor Receptor Antagonism in Head and Neck Squamous Carcinoma Cells

Targeting Insulin-Like Growth Factor Binding Protein-3 Signaling in Triple-Negative Breast Cancer

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