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STAT3 regulated ARF expression suppresses prostate cancer metastasis.

Pencik J, Schlederer M, Gruber W, Unger C, Walker SM, Chalaris A, Marié IJ, Hassler MR, Javaheri T, Aksoy O, Blayney JK, Prutsch N, Skucha A, Herac M, Krämer OH, Mazal P, Grebien F, Egger G, Poli V, Mikulits W, Eferl R, Esterbauer H, Kennedy R, Fend F, Scharpf M, Braun M, Perner S, Levy DE, Malcolm T, Turner SD, Haitel A, Susani M, Moazzami A, Rose-John S, Aberger F, Merkel O, Moriggl R, Culig Z, Dolznig H, Kenner L - Nat Commun (2015)

Bottom Line: However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit.STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases.Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.

View Article: PubMed Central - PubMed

Affiliation: Ludwig Boltzmann Institute for Cancer Research, Waehringerstrasse 13A, 1090 Vienna, Austria.

ABSTRACT
Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19(ARF) as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF-Mdm2-p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14(ARF) expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.

No MeSH data available.


Related in: MedlinePlus

JAK1/2 inhibition promotes tumour progression and decreases STAT3 and p14ARF expression.(a) Gross anatomy of representative LNCaP xenograft tumours treated with ruxolitinib. Mice bearing xenografts were treated with a vehicle or 50 mg kg−1 ruxolitinib. Scale bars, 10 mm. (b) Tumour weight of vehicle-treated mice versus ruxolitinib treatment for 22 days of age-matched SCID beige mice. Mean values are shown; error bars: s.d. (n=3). (c) IHC stainings of Ki-67, STAT3 and p14ARF expression in vehicle versus ruxolitinib-treated xenografted tumours (n=3), scale bar 50 μm. (d) LNCaP cells treated with control (DMSO) or 10 μM ruxolitinib were grown in soft agar for 12 days. Mean values are shown; error bars: s.d. (n=4). Data from b and d were analysed by Student's t-test.
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f6: JAK1/2 inhibition promotes tumour progression and decreases STAT3 and p14ARF expression.(a) Gross anatomy of representative LNCaP xenograft tumours treated with ruxolitinib. Mice bearing xenografts were treated with a vehicle or 50 mg kg−1 ruxolitinib. Scale bars, 10 mm. (b) Tumour weight of vehicle-treated mice versus ruxolitinib treatment for 22 days of age-matched SCID beige mice. Mean values are shown; error bars: s.d. (n=3). (c) IHC stainings of Ki-67, STAT3 and p14ARF expression in vehicle versus ruxolitinib-treated xenografted tumours (n=3), scale bar 50 μm. (d) LNCaP cells treated with control (DMSO) or 10 μM ruxolitinib were grown in soft agar for 12 days. Mean values are shown; error bars: s.d. (n=4). Data from b and d were analysed by Student's t-test.

Mentions: Intriguingly, in vivo blocking of IL-6/STAT3 signalling by the JAK1/2 inhibitor ruxolitinib in human LNCaP xenografts showed significantly enhanced tumour size and weight (Fig. 6a,b). The ruxolitinib-treated xenografts also had markedly increased numbers of Ki-67+ cancer cells accompanied by a decrease in STAT3 and p14ARF expression (Fig. 6c). Moreover, ruxolitinib treatment of LNCaP cells significantly promoted colony formation (Fig. 6d). Of note, LNCaP cells lack JAK1 expression and do not respond to interferon signalling31. Moreover, STAT3 was shown to be activated in xenografts of LNCaP cells, most likely due to the sole action of JAK2 (refs 32, 33). Ruxolitinib is a dual-specific JAK1/2 kinase inhibitor and therefore, effects of ruxolitinib on the LNCaP xenograft model are likely to be a consequence of JAK2/STAT3 inhibition independent of IFN gamma signalling.


STAT3 regulated ARF expression suppresses prostate cancer metastasis.

Pencik J, Schlederer M, Gruber W, Unger C, Walker SM, Chalaris A, Marié IJ, Hassler MR, Javaheri T, Aksoy O, Blayney JK, Prutsch N, Skucha A, Herac M, Krämer OH, Mazal P, Grebien F, Egger G, Poli V, Mikulits W, Eferl R, Esterbauer H, Kennedy R, Fend F, Scharpf M, Braun M, Perner S, Levy DE, Malcolm T, Turner SD, Haitel A, Susani M, Moazzami A, Rose-John S, Aberger F, Merkel O, Moriggl R, Culig Z, Dolznig H, Kenner L - Nat Commun (2015)

JAK1/2 inhibition promotes tumour progression and decreases STAT3 and p14ARF expression.(a) Gross anatomy of representative LNCaP xenograft tumours treated with ruxolitinib. Mice bearing xenografts were treated with a vehicle or 50 mg kg−1 ruxolitinib. Scale bars, 10 mm. (b) Tumour weight of vehicle-treated mice versus ruxolitinib treatment for 22 days of age-matched SCID beige mice. Mean values are shown; error bars: s.d. (n=3). (c) IHC stainings of Ki-67, STAT3 and p14ARF expression in vehicle versus ruxolitinib-treated xenografted tumours (n=3), scale bar 50 μm. (d) LNCaP cells treated with control (DMSO) or 10 μM ruxolitinib were grown in soft agar for 12 days. Mean values are shown; error bars: s.d. (n=4). Data from b and d were analysed by Student's t-test.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4525303&req=5

f6: JAK1/2 inhibition promotes tumour progression and decreases STAT3 and p14ARF expression.(a) Gross anatomy of representative LNCaP xenograft tumours treated with ruxolitinib. Mice bearing xenografts were treated with a vehicle or 50 mg kg−1 ruxolitinib. Scale bars, 10 mm. (b) Tumour weight of vehicle-treated mice versus ruxolitinib treatment for 22 days of age-matched SCID beige mice. Mean values are shown; error bars: s.d. (n=3). (c) IHC stainings of Ki-67, STAT3 and p14ARF expression in vehicle versus ruxolitinib-treated xenografted tumours (n=3), scale bar 50 μm. (d) LNCaP cells treated with control (DMSO) or 10 μM ruxolitinib were grown in soft agar for 12 days. Mean values are shown; error bars: s.d. (n=4). Data from b and d were analysed by Student's t-test.
Mentions: Intriguingly, in vivo blocking of IL-6/STAT3 signalling by the JAK1/2 inhibitor ruxolitinib in human LNCaP xenografts showed significantly enhanced tumour size and weight (Fig. 6a,b). The ruxolitinib-treated xenografts also had markedly increased numbers of Ki-67+ cancer cells accompanied by a decrease in STAT3 and p14ARF expression (Fig. 6c). Moreover, ruxolitinib treatment of LNCaP cells significantly promoted colony formation (Fig. 6d). Of note, LNCaP cells lack JAK1 expression and do not respond to interferon signalling31. Moreover, STAT3 was shown to be activated in xenografts of LNCaP cells, most likely due to the sole action of JAK2 (refs 32, 33). Ruxolitinib is a dual-specific JAK1/2 kinase inhibitor and therefore, effects of ruxolitinib on the LNCaP xenograft model are likely to be a consequence of JAK2/STAT3 inhibition independent of IFN gamma signalling.

Bottom Line: However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit.STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases.Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.

View Article: PubMed Central - PubMed

Affiliation: Ludwig Boltzmann Institute for Cancer Research, Waehringerstrasse 13A, 1090 Vienna, Austria.

ABSTRACT
Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19(ARF) as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF-Mdm2-p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14(ARF) expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.

No MeSH data available.


Related in: MedlinePlus