JAK-STAT blockade inhibits tumor initiation and clonogenic recovery of prostate cancer stem-like cells
Interleukin (IL)-6 overexpression and constitutive STAT3 activation occur in many cancers, including prostate cancer. However, their contribution to prostate stem and progenitor cells has not been explored. In this study, we show that stem-like cells from patients with prostate cancer secrete higher levels of IL-6 than their counterparts in non-neoplastic prostate. Tumor grade did not influence the levels of expression or secretion. Stem-like and progenitor cells expressed the IL-6 receptor gp80 with concomitant expression of pSTAT3. Blockade of activated STAT3, by either anti-IL-6 antibody siltuximab (CNTO 328) or LLL12, a specific pSTAT3 inhibitor, suppressed the clonogenicity of the stem-like cells in patients with high-grade disease. In a murine xenograft model used to determine the in vivo effects of pSTAT3 suppression, LLL12 treatment effectively abolished outgrowth of a patient-derived castrate-resistant tumor. Our results indicate that the most primitive cells in prostate cancer require pSTAT3 for survival, rationalizing STAT3 as a therapeutic target to treat advanced prostate cancer.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2013 |
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| Erschienen: |
2013 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:73 |
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| Enthalten in: |
Cancer research - 73(2013), 16 vom: 15. Aug., Seite 5288-98 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kroon, Paula [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 20.02.2014 Date Revised 31.03.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1158/0008-5472.CAN-13-0874 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM228882672 |
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| 100 | 1 | |a Kroon, Paula |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a JAK-STAT blockade inhibits tumor initiation and clonogenic recovery of prostate cancer stem-like cells |
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| 500 | |a Date Revised 31.03.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Interleukin (IL)-6 overexpression and constitutive STAT3 activation occur in many cancers, including prostate cancer. However, their contribution to prostate stem and progenitor cells has not been explored. In this study, we show that stem-like cells from patients with prostate cancer secrete higher levels of IL-6 than their counterparts in non-neoplastic prostate. Tumor grade did not influence the levels of expression or secretion. Stem-like and progenitor cells expressed the IL-6 receptor gp80 with concomitant expression of pSTAT3. Blockade of activated STAT3, by either anti-IL-6 antibody siltuximab (CNTO 328) or LLL12, a specific pSTAT3 inhibitor, suppressed the clonogenicity of the stem-like cells in patients with high-grade disease. In a murine xenograft model used to determine the in vivo effects of pSTAT3 suppression, LLL12 treatment effectively abolished outgrowth of a patient-derived castrate-resistant tumor. Our results indicate that the most primitive cells in prostate cancer require pSTAT3 for survival, rationalizing STAT3 as a therapeutic target to treat advanced prostate cancer | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Anthraquinones |2 NLM | |
| 650 | 7 | |a Antibodies, Monoclonal |2 NLM | |
| 650 | 7 | |a IL6 protein, human |2 NLM | |
| 650 | 7 | |a IL6R protein, human |2 NLM | |
| 650 | 7 | |a Interleukin-6 |2 NLM | |
| 650 | 7 | |a LLL12 compound |2 NLM | |
| 650 | 7 | |a Receptors, Interleukin-6 |2 NLM | |
| 650 | 7 | |a STAT3 Transcription Factor |2 NLM | |
| 650 | 7 | |a STAT3 protein, human |2 NLM | |
| 650 | 7 | |a Sulfonamides |2 NLM | |
| 650 | 7 | |a Janus Kinases |2 NLM | |
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| 700 | 1 | |a Berry, Paul A |e verfasserin |4 aut | |
| 700 | 1 | |a Stower, Michael J |e verfasserin |4 aut | |
| 700 | 1 | |a Rodrigues, Greta |e verfasserin |4 aut | |
| 700 | 1 | |a Mann, Vincent M |e verfasserin |4 aut | |
| 700 | 1 | |a Simms, Matthew |e verfasserin |4 aut | |
| 700 | 1 | |a Bhasin, Deepak |e verfasserin |4 aut | |
| 700 | 1 | |a Chettiar, Somsundaram |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Chenglong |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Pui-Kai |e verfasserin |4 aut | |
| 700 | 1 | |a Maitland, Norman J |e verfasserin |4 aut | |
| 700 | 1 | |a Collins, Anne T |e verfasserin |4 aut | |
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