Inhibition of STAT3 by Anticancer Drug Bendamustine.
Bendamustine (BENDA), which bears the bis(2-chloroethyl)amino moiety, is an alkylating agent that stops the growth of cancer cells by binding to DNA and interfering with its replication. However, the mechanism of action underlying its excellent clinical efficacy remains unclear. In this work, we rep...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2017-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5268383?pdf=render |
| _version_ | 1818856505594609664 |
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| author | Kazunori Iwamoto Yutaka Uehara Yukie Inoue Kyoko Taguchi Daisuke Muraoka Naohisa Ogo Kenji Matsuno Akira Asai |
| author_facet | Kazunori Iwamoto Yutaka Uehara Yukie Inoue Kyoko Taguchi Daisuke Muraoka Naohisa Ogo Kenji Matsuno Akira Asai |
| author_sort | Kazunori Iwamoto |
| collection | DOAJ |
| description | Bendamustine (BENDA), which bears the bis(2-chloroethyl)amino moiety, is an alkylating agent that stops the growth of cancer cells by binding to DNA and interfering with its replication. However, the mechanism of action underlying its excellent clinical efficacy remains unclear. In this work, we report that BENDA inhibits signal transducer and activator of transcription 3 (STAT3). In an AlphaScreen-based biochemical assay using recombinant human STAT3, binding of STAT3-Src homology 2 (SH2) to the phosphotyrosine (pTyr, pY) peptide was inhibited by BENDA but not by the inactive metabolite dihydroxy bendamustine (HP2). When a single point mutation of C550A or C712A was introduced into recombinant human STAT3, its sensitivity to BENDA was substantially reduced, suggesting that these cysteine residues are important for BENDA to inhibit STAT3. Furthermore, BENDA suppressed the function of cellular STAT3 as a transcriptional activator in a human breast cancer cell line, MDA-MB-468, with constitutively activated STAT3. A competitive pull-down assay using biotinylated BENDA (Bio-BENDA) revealed that BENDA bound tightly to cellular STAT3, presumably through covalent bonds. Therefore, our results suggest that the anticancer effects of BENDA may be associated, at least in part, with its inhibitory effect on the SH2 domain of STAT3. |
| first_indexed | 2024-12-19T08:25:34Z |
| format | Article |
| id | doaj.art-bf860007ca6c49be8d5ff1910c64fb75 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-19T08:25:34Z |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-bf860007ca6c49be8d5ff1910c64fb752022-12-21T20:29:19ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01121e017070910.1371/journal.pone.0170709Inhibition of STAT3 by Anticancer Drug Bendamustine.Kazunori IwamotoYutaka UeharaYukie InoueKyoko TaguchiDaisuke MuraokaNaohisa OgoKenji MatsunoAkira AsaiBendamustine (BENDA), which bears the bis(2-chloroethyl)amino moiety, is an alkylating agent that stops the growth of cancer cells by binding to DNA and interfering with its replication. However, the mechanism of action underlying its excellent clinical efficacy remains unclear. In this work, we report that BENDA inhibits signal transducer and activator of transcription 3 (STAT3). In an AlphaScreen-based biochemical assay using recombinant human STAT3, binding of STAT3-Src homology 2 (SH2) to the phosphotyrosine (pTyr, pY) peptide was inhibited by BENDA but not by the inactive metabolite dihydroxy bendamustine (HP2). When a single point mutation of C550A or C712A was introduced into recombinant human STAT3, its sensitivity to BENDA was substantially reduced, suggesting that these cysteine residues are important for BENDA to inhibit STAT3. Furthermore, BENDA suppressed the function of cellular STAT3 as a transcriptional activator in a human breast cancer cell line, MDA-MB-468, with constitutively activated STAT3. A competitive pull-down assay using biotinylated BENDA (Bio-BENDA) revealed that BENDA bound tightly to cellular STAT3, presumably through covalent bonds. Therefore, our results suggest that the anticancer effects of BENDA may be associated, at least in part, with its inhibitory effect on the SH2 domain of STAT3.http://europepmc.org/articles/PMC5268383?pdf=render |
| spellingShingle | Kazunori Iwamoto Yutaka Uehara Yukie Inoue Kyoko Taguchi Daisuke Muraoka Naohisa Ogo Kenji Matsuno Akira Asai Inhibition of STAT3 by Anticancer Drug Bendamustine. PLoS ONE |
| title | Inhibition of STAT3 by Anticancer Drug Bendamustine. |
| title_full | Inhibition of STAT3 by Anticancer Drug Bendamustine. |
| title_fullStr | Inhibition of STAT3 by Anticancer Drug Bendamustine. |
| title_full_unstemmed | Inhibition of STAT3 by Anticancer Drug Bendamustine. |
| title_short | Inhibition of STAT3 by Anticancer Drug Bendamustine. |
| title_sort | inhibition of stat3 by anticancer drug bendamustine |
| url | http://europepmc.org/articles/PMC5268383?pdf=render |
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