Frenolicin B Targets Peroxiredoxin 1 and Glutaredoxin 3 to Trigger ROS/4E-BP1-Mediated Antitumor Effects

Qing Ye; Yinan Zhang; Yanan Cao; Xiachang Wang; Yubin Guo; Jing Chen; Jamie Horn; Larissa V. Ponomareva; Luksana Chaiswing; Khaled A. Shaaban; Qiou Wei; Bradley D. Anderson; Daret K. St Clair; Haining Zhu; Markos Leggas; Jon S. Thorson; Qing Bai She

doi:10.1016/j.chembiol.2018.11.013

Frenolicin B Targets Peroxiredoxin 1 and Glutaredoxin 3 to Trigger ROS/4E-BP1-Mediated Antitumor Effects

Qing Ye, Yinan Zhang, Yanan Cao, Xiachang Wang, Yubin Guo, Jing Chen, Jamie Horn, Larissa V. Ponomareva, Luksana Chaiswing, Khaled A. Shaaban, Qiou Wei, Bradley D. Anderson, Daret K. St Clair, Haining Zhu, Markos Leggas, Jon S. Thorson, Qing Bai She

Research output: Contribution to journal › Article › peer-review

22 Citations (SciVal)

Abstract

Peroxiredoxin 1 (Prx1) and glutaredoxin 3 (Grx3) are two major antioxidant proteins that play a critical role in maintaining redox homeostasis for tumor progression. Here, we identify the prototypical pyranonaphthoquinone natural product frenolicin B (FB) as a selective inhibitor of Prx1 and Grx3 through covalent modification of active-site cysteines. FB-targeted inhibition of Prx1 and Grx3 results in a decrease in cellular glutathione levels, an increase of reactive oxygen species (ROS), and concomitant inhibition of cancer cell growth, largely by activating the peroxisome-bound tuberous sclerosis complex to inhibit mTORC1/4E-BP1 signaling axis. FB structure-activity relationship studies reveal a positive correlation between inhibition of 4E-BP1 phosphorylation, ROS-mediated cancer cell cytotoxicity, and suppression of tumor growth in vivo. These findings establish FB as the most potent Prx1/Grx3 inhibitor reported to date and also notably highlight 4E-BP1 phosphorylation status as a potential predictive marker in response to ROS-based therapies in cancer. Ye, Zhang et al. identify frenolicin B as a potent and selective inhibitor of Prx1 and Grx3, leading to generation of ROS and subsequent repression of mTORC1/4E-BP1-mediated translational control of tumor growth with the potential to be developed into a new class of anticancer agents.

Original language	English
Pages (from-to)	366-377.e12
Journal	Cell Chemical Biology
Volume	26
Issue number	3
DOIs	https://doi.org/10.1016/j.chembiol.2018.11.013
State	Published - Mar 21 2019

Bibliographical note

Funding Information:
This work was supported, in part, by NIH grants CA203257 (J.S.T and Q.-B.S.), CA175105 (Q.-B.S.), T32 DA016176 (Y.Z.), CCSG (P30CA177558) pilot funding (Q.-B.S.), the National Center for Advancing Translational Sciences (UL1TR000117, UL1TR001998), and the University of Kentucky College of Pharmacy and Markey Cancer Center. The authors also acknowledge use of the University of Kentucky Flow Cytometry & Cell Sorting core facility, supported in part by the Office of the Vice President for Research, the Markey Cancer Center, and an NCI Center Core support grant (P30CA177558).

Funding Information:
This work was supported, in part, by NIH grants CA203257 (J.S.T and Q.-B.S.), CA175105 (Q.-B.S.), T32 DA016176 (Y.Z.), CCSG ( P30CA177558 ) pilot funding (Q.-B.S.), the National Center for Advancing Translational Sciences ( UL1TR000117 , UL1TR001998 ), and the University of Kentucky College of Pharmacy and Markey Cancer Center . The authors also acknowledge use of the University of Kentucky Flow Cytometry & Cell Sorting core facility, supported in part by the Office of the Vice President for Research , the Markey Cancer Center, and an NCI Center Core support grant ( P30CA177558 ).

Publisher Copyright:
© 2018

Keywords

4E-BP1
AKT
RAS
ROS
eIF4E
frenolicin B
glutaredoxin 3
mTORC1
peroxiredoxin 1
pyranonaphthoquinone

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.chembiol.2018.11.013

Cite this

Ye, Q., Zhang, Y., Cao, Y., Wang, X., Guo, Y., Chen, J., Horn, J., Ponomareva, L. V., Chaiswing, L., Shaaban, K. A., Wei, Q., Anderson, B. D., St Clair, D. K., Zhu, H., Leggas, M., Thorson, J. S., & She, Q. B. (2019). Frenolicin B Targets Peroxiredoxin 1 and Glutaredoxin 3 to Trigger ROS/4E-BP1-Mediated Antitumor Effects. Cell Chemical Biology, 26(3), 366-377.e12. https://doi.org/10.1016/j.chembiol.2018.11.013

@article{eb366ac4ef0444adbd874ae306e97c46,

title = "Frenolicin B Targets Peroxiredoxin 1 and Glutaredoxin 3 to Trigger ROS/4E-BP1-Mediated Antitumor Effects",

abstract = "Peroxiredoxin 1 (Prx1) and glutaredoxin 3 (Grx3) are two major antioxidant proteins that play a critical role in maintaining redox homeostasis for tumor progression. Here, we identify the prototypical pyranonaphthoquinone natural product frenolicin B (FB) as a selective inhibitor of Prx1 and Grx3 through covalent modification of active-site cysteines. FB-targeted inhibition of Prx1 and Grx3 results in a decrease in cellular glutathione levels, an increase of reactive oxygen species (ROS), and concomitant inhibition of cancer cell growth, largely by activating the peroxisome-bound tuberous sclerosis complex to inhibit mTORC1/4E-BP1 signaling axis. FB structure-activity relationship studies reveal a positive correlation between inhibition of 4E-BP1 phosphorylation, ROS-mediated cancer cell cytotoxicity, and suppression of tumor growth in vivo. These findings establish FB as the most potent Prx1/Grx3 inhibitor reported to date and also notably highlight 4E-BP1 phosphorylation status as a potential predictive marker in response to ROS-based therapies in cancer. Ye, Zhang et al. identify frenolicin B as a potent and selective inhibitor of Prx1 and Grx3, leading to generation of ROS and subsequent repression of mTORC1/4E-BP1-mediated translational control of tumor growth with the potential to be developed into a new class of anticancer agents.",

keywords = "4E-BP1, AKT, RAS, ROS, eIF4E, frenolicin B, glutaredoxin 3, mTORC1, peroxiredoxin 1, pyranonaphthoquinone",

author = "Qing Ye and Yinan Zhang and Yanan Cao and Xiachang Wang and Yubin Guo and Jing Chen and Jamie Horn and Ponomareva, {Larissa V.} and Luksana Chaiswing and Shaaban, {Khaled A.} and Qiou Wei and Anderson, {Bradley D.} and {St Clair}, {Daret K.} and Haining Zhu and Markos Leggas and Thorson, {Jon S.} and She, {Qing Bai}",

note = "Funding Information: This work was supported, in part, by NIH grants CA203257 (J.S.T and Q.-B.S.), CA175105 (Q.-B.S.), T32 DA016176 (Y.Z.), CCSG (P30CA177558) pilot funding (Q.-B.S.), the National Center for Advancing Translational Sciences (UL1TR000117, UL1TR001998), and the University of Kentucky College of Pharmacy and Markey Cancer Center. The authors also acknowledge use of the University of Kentucky Flow Cytometry & Cell Sorting core facility, supported in part by the Office of the Vice President for Research, the Markey Cancer Center, and an NCI Center Core support grant (P30CA177558). Funding Information: This work was supported, in part, by NIH grants CA203257 (J.S.T and Q.-B.S.), CA175105 (Q.-B.S.), T32 DA016176 (Y.Z.), CCSG ( P30CA177558 ) pilot funding (Q.-B.S.), the National Center for Advancing Translational Sciences ( UL1TR000117 , UL1TR001998 ), and the University of Kentucky College of Pharmacy and Markey Cancer Center . The authors also acknowledge use of the University of Kentucky Flow Cytometry & Cell Sorting core facility, supported in part by the Office of the Vice President for Research , the Markey Cancer Center, and an NCI Center Core support grant ( P30CA177558 ). Publisher Copyright: {\textcopyright} 2018",

year = "2019",

month = mar,

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doi = "10.1016/j.chembiol.2018.11.013",

language = "English",

volume = "26",

pages = "366--377.e12",

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Ye, Q, Zhang, Y, Cao, Y, Wang, X, Guo, Y, Chen, J, Horn, J, Ponomareva, LV, Chaiswing, L , Shaaban, KA , Wei, Q, Anderson, BD, St Clair, DK, Zhu, H, Leggas, M, Thorson, JS & She, QB 2019, 'Frenolicin B Targets Peroxiredoxin 1 and Glutaredoxin 3 to Trigger ROS/4E-BP1-Mediated Antitumor Effects', Cell Chemical Biology, vol. 26, no. 3, pp. 366-377.e12. https://doi.org/10.1016/j.chembiol.2018.11.013

TY - JOUR

T1 - Frenolicin B Targets Peroxiredoxin 1 and Glutaredoxin 3 to Trigger ROS/4E-BP1-Mediated Antitumor Effects

AU - Ye, Qing

AU - Zhang, Yinan

AU - Cao, Yanan

AU - Wang, Xiachang

AU - Guo, Yubin

AU - Chen, Jing

AU - Horn, Jamie

AU - Ponomareva, Larissa V.

AU - Chaiswing, Luksana

AU - Shaaban, Khaled A.

AU - Wei, Qiou

AU - Anderson, Bradley D.

AU - St Clair, Daret K.

AU - Zhu, Haining

AU - Leggas, Markos

AU - Thorson, Jon S.

AU - She, Qing Bai

N1 - Funding Information: This work was supported, in part, by NIH grants CA203257 (J.S.T and Q.-B.S.), CA175105 (Q.-B.S.), T32 DA016176 (Y.Z.), CCSG (P30CA177558) pilot funding (Q.-B.S.), the National Center for Advancing Translational Sciences (UL1TR000117, UL1TR001998), and the University of Kentucky College of Pharmacy and Markey Cancer Center. The authors also acknowledge use of the University of Kentucky Flow Cytometry & Cell Sorting core facility, supported in part by the Office of the Vice President for Research, the Markey Cancer Center, and an NCI Center Core support grant (P30CA177558). Funding Information: This work was supported, in part, by NIH grants CA203257 (J.S.T and Q.-B.S.), CA175105 (Q.-B.S.), T32 DA016176 (Y.Z.), CCSG ( P30CA177558 ) pilot funding (Q.-B.S.), the National Center for Advancing Translational Sciences ( UL1TR000117 , UL1TR001998 ), and the University of Kentucky College of Pharmacy and Markey Cancer Center . The authors also acknowledge use of the University of Kentucky Flow Cytometry & Cell Sorting core facility, supported in part by the Office of the Vice President for Research , the Markey Cancer Center, and an NCI Center Core support grant ( P30CA177558 ). Publisher Copyright: © 2018

PY - 2019/3/21

Y1 - 2019/3/21

N2 - Peroxiredoxin 1 (Prx1) and glutaredoxin 3 (Grx3) are two major antioxidant proteins that play a critical role in maintaining redox homeostasis for tumor progression. Here, we identify the prototypical pyranonaphthoquinone natural product frenolicin B (FB) as a selective inhibitor of Prx1 and Grx3 through covalent modification of active-site cysteines. FB-targeted inhibition of Prx1 and Grx3 results in a decrease in cellular glutathione levels, an increase of reactive oxygen species (ROS), and concomitant inhibition of cancer cell growth, largely by activating the peroxisome-bound tuberous sclerosis complex to inhibit mTORC1/4E-BP1 signaling axis. FB structure-activity relationship studies reveal a positive correlation between inhibition of 4E-BP1 phosphorylation, ROS-mediated cancer cell cytotoxicity, and suppression of tumor growth in vivo. These findings establish FB as the most potent Prx1/Grx3 inhibitor reported to date and also notably highlight 4E-BP1 phosphorylation status as a potential predictive marker in response to ROS-based therapies in cancer. Ye, Zhang et al. identify frenolicin B as a potent and selective inhibitor of Prx1 and Grx3, leading to generation of ROS and subsequent repression of mTORC1/4E-BP1-mediated translational control of tumor growth with the potential to be developed into a new class of anticancer agents.

AB - Peroxiredoxin 1 (Prx1) and glutaredoxin 3 (Grx3) are two major antioxidant proteins that play a critical role in maintaining redox homeostasis for tumor progression. Here, we identify the prototypical pyranonaphthoquinone natural product frenolicin B (FB) as a selective inhibitor of Prx1 and Grx3 through covalent modification of active-site cysteines. FB-targeted inhibition of Prx1 and Grx3 results in a decrease in cellular glutathione levels, an increase of reactive oxygen species (ROS), and concomitant inhibition of cancer cell growth, largely by activating the peroxisome-bound tuberous sclerosis complex to inhibit mTORC1/4E-BP1 signaling axis. FB structure-activity relationship studies reveal a positive correlation between inhibition of 4E-BP1 phosphorylation, ROS-mediated cancer cell cytotoxicity, and suppression of tumor growth in vivo. These findings establish FB as the most potent Prx1/Grx3 inhibitor reported to date and also notably highlight 4E-BP1 phosphorylation status as a potential predictive marker in response to ROS-based therapies in cancer. Ye, Zhang et al. identify frenolicin B as a potent and selective inhibitor of Prx1 and Grx3, leading to generation of ROS and subsequent repression of mTORC1/4E-BP1-mediated translational control of tumor growth with the potential to be developed into a new class of anticancer agents.

KW - 4E-BP1

KW - AKT

KW - RAS

KW - ROS

KW - eIF4E

KW - frenolicin B

KW - glutaredoxin 3

KW - mTORC1

KW - peroxiredoxin 1

KW - pyranonaphthoquinone

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DO - 10.1016/j.chembiol.2018.11.013

M3 - Article

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VL - 26

SP - 366-377.e12

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ER -

Frenolicin B Targets Peroxiredoxin 1 and Glutaredoxin 3 to Trigger ROS/4E-BP1-Mediated Antitumor Effects

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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