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Pharmacological Targeting SHP-1-STAT3 Signaling Is a Promising Therapeutic Approach for the Treatment of Colorectal Cancer()()
STAT3 activation is associated with poor prognosis in human colorectal cancer (CRC). Our previous data demonstrated that regorafenib (Stivarga) is a pharmacological agonist of SH2 domain-containing phosphatase 1 (SHP-1) that enhances SHP-1 activity and induces apoptosis by targeting STAT3 signals in...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Neoplasia Press
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4611073/ https://www.ncbi.nlm.nih.gov/pubmed/26476076 http://dx.doi.org/10.1016/j.neo.2015.08.007 |
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author | Fan, Li-Ching Teng, Hao-Wei Shiau, Chung-Wai Tai, Wei-Tien Hung, Man-Hsin Yang, Shung-Haur Jiang, Jeng-Kai Chen, Kuen-Feng |
author_facet | Fan, Li-Ching Teng, Hao-Wei Shiau, Chung-Wai Tai, Wei-Tien Hung, Man-Hsin Yang, Shung-Haur Jiang, Jeng-Kai Chen, Kuen-Feng |
author_sort | Fan, Li-Ching |
collection | PubMed |
description | STAT3 activation is associated with poor prognosis in human colorectal cancer (CRC). Our previous data demonstrated that regorafenib (Stivarga) is a pharmacological agonist of SH2 domain-containing phosphatase 1 (SHP-1) that enhances SHP-1 activity and induces apoptosis by targeting STAT3 signals in CRC. This study aimed to find a therapeutic drug that is more effective than regorafenib for CRC treatment. Here, we showed that SC-43 was more effective than regorafenib at inducing apoptosis in vitro and suppressing tumorigenesis in vivo. SC-43 significantly increased SHP-1 activity, downregulated p-STAT3(Tyr705) level, and induced apoptosis in CRC cells. An SHP-1 inhibitor or knockdown of SHP-1 by siRNA both significantly rescued the SC-43–induced apoptosis and decreased p-STAT3(Tyr705) level. Conversely, SHP-1 overexpression increased the effects of SC-43 on apoptosis and p-STAT3(Tyr705) level. These data suggest that SC-43–induced apoptosis mediated through the loss of p-STAT3(Tyr705) was dependent on SHP-1 function. Importantly, SC-43–enhanced SHP-1 activity was because of the docking potential of SC-43, which relieved the autoinhibited N-SH2 domain of SHP-1 and inhibited p-STAT3(Tyr705) signals. Importantly, we observed that a significant negative correlation existed between SHP-1 and p-STAT3(Tyr705)expression in CRC patients (P = .038). Patients with strong SHP-1 and weak p-STAT3(Tyr705) expression had significantly higher overall survival compared with patients with weak SHP-1 and strong p-STAT3(Tyr705) expression (P = .029). In conclusion, SHP-1 is suitable to be a useful prognostic marker and a pharmacological target for CRC treatment. Targeting SHP-1-STAT3 signaling by SC-43 may serve as a promising pharmacotherapy for CRC. |
format | Online Article Text |
id | pubmed-4611073 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Neoplasia Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-46110732015-11-10 Pharmacological Targeting SHP-1-STAT3 Signaling Is a Promising Therapeutic Approach for the Treatment of Colorectal Cancer()() Fan, Li-Ching Teng, Hao-Wei Shiau, Chung-Wai Tai, Wei-Tien Hung, Man-Hsin Yang, Shung-Haur Jiang, Jeng-Kai Chen, Kuen-Feng Neoplasia Article STAT3 activation is associated with poor prognosis in human colorectal cancer (CRC). Our previous data demonstrated that regorafenib (Stivarga) is a pharmacological agonist of SH2 domain-containing phosphatase 1 (SHP-1) that enhances SHP-1 activity and induces apoptosis by targeting STAT3 signals in CRC. This study aimed to find a therapeutic drug that is more effective than regorafenib for CRC treatment. Here, we showed that SC-43 was more effective than regorafenib at inducing apoptosis in vitro and suppressing tumorigenesis in vivo. SC-43 significantly increased SHP-1 activity, downregulated p-STAT3(Tyr705) level, and induced apoptosis in CRC cells. An SHP-1 inhibitor or knockdown of SHP-1 by siRNA both significantly rescued the SC-43–induced apoptosis and decreased p-STAT3(Tyr705) level. Conversely, SHP-1 overexpression increased the effects of SC-43 on apoptosis and p-STAT3(Tyr705) level. These data suggest that SC-43–induced apoptosis mediated through the loss of p-STAT3(Tyr705) was dependent on SHP-1 function. Importantly, SC-43–enhanced SHP-1 activity was because of the docking potential of SC-43, which relieved the autoinhibited N-SH2 domain of SHP-1 and inhibited p-STAT3(Tyr705) signals. Importantly, we observed that a significant negative correlation existed between SHP-1 and p-STAT3(Tyr705)expression in CRC patients (P = .038). Patients with strong SHP-1 and weak p-STAT3(Tyr705) expression had significantly higher overall survival compared with patients with weak SHP-1 and strong p-STAT3(Tyr705) expression (P = .029). In conclusion, SHP-1 is suitable to be a useful prognostic marker and a pharmacological target for CRC treatment. Targeting SHP-1-STAT3 signaling by SC-43 may serve as a promising pharmacotherapy for CRC. Neoplasia Press 2015-10-19 /pmc/articles/PMC4611073/ /pubmed/26476076 http://dx.doi.org/10.1016/j.neo.2015.08.007 Text en © 2015 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Fan, Li-Ching Teng, Hao-Wei Shiau, Chung-Wai Tai, Wei-Tien Hung, Man-Hsin Yang, Shung-Haur Jiang, Jeng-Kai Chen, Kuen-Feng Pharmacological Targeting SHP-1-STAT3 Signaling Is a Promising Therapeutic Approach for the Treatment of Colorectal Cancer()() |
title | Pharmacological Targeting SHP-1-STAT3 Signaling Is a Promising Therapeutic Approach for the Treatment of Colorectal Cancer()() |
title_full | Pharmacological Targeting SHP-1-STAT3 Signaling Is a Promising Therapeutic Approach for the Treatment of Colorectal Cancer()() |
title_fullStr | Pharmacological Targeting SHP-1-STAT3 Signaling Is a Promising Therapeutic Approach for the Treatment of Colorectal Cancer()() |
title_full_unstemmed | Pharmacological Targeting SHP-1-STAT3 Signaling Is a Promising Therapeutic Approach for the Treatment of Colorectal Cancer()() |
title_short | Pharmacological Targeting SHP-1-STAT3 Signaling Is a Promising Therapeutic Approach for the Treatment of Colorectal Cancer()() |
title_sort | pharmacological targeting shp-1-stat3 signaling is a promising therapeutic approach for the treatment of colorectal cancer()() |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4611073/ https://www.ncbi.nlm.nih.gov/pubmed/26476076 http://dx.doi.org/10.1016/j.neo.2015.08.007 |
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