TY - JOUR
T1 - Sorafenib targets the mitochondrial electron transport chain complexes and ATP synthase to activate the PINK1-Parkin pathway and modulate cellular drug response
AU - Zhang, Conggang
AU - Liu, Zeyu
AU - Bunker, Eric
AU - Ramirez, Adrian
AU - Lee, Schuyler
AU - Peng, Yinghua
AU - Tan, Aik Choon
AU - Eckhardt, S. Gail
AU - Chapnick, Douglas A.
AU - Liu, Xuedong
N1 - Funding Information:
This work was supported by National Institutes of Health Grant GM113141 and a Butcher Award from the University of Colorado (to X. L.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Information:
Acknowledgments—We thank Drs. Stratford May, Jie Shen, Stefan Constantinescu, Schuyler Van Engelenburg, Jennifer Lippincott-Schwartz, and Sabrina Spencer for providing critical reagents. We thank Drs. Natalie Ahn, Amy Palmer, and Douglas Chapnick for discussion. We thank Graycen Wheeler for critical reading of the manuscript. We thank Steve Wiltgen and Vipat Raksakulthai of Molecular Devices for their help with development of MetaXpress journals for automated imaging analysis. The ImageXpress MicroXL was supported by National Institutes of Health Grant S10 RR026680 from NCRR. We thank Joseph Dragavon and BioFrontiers Advanced Light Microscopy Core for their support. The FACSAria cell sorter was supported by National Institutes of Health Grant S10 OD021601.
Publisher Copyright:
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2017/9/8
Y1 - 2017/9/8
N2 - Sorafenib (Nexavar) is a broad-spectrum multikinase inhibitor that proves effective in treating advanced renal-cell carcinoma and liver cancer. Despite its well-characterized mechanism of action on several established cancer-related protein kinases, sorafenib causes variable responses among human tumors, although the cause for this variation is unknown. In an unbiased screening of an oncology drug library, we found that sorafenib activates recruitment of the ubiquitin E3 ligase Parkin to damaged mitochondria. We show that sorafenib inhibits the activity of both complex II/III of the electron transport chain and ATP synthase. Dual inhibition of these complexes, but not inhibition of each individual complex, stabilizes the serine-threonine protein kinase PINK1 on the mitochondrial outer membrane and activates Parkin. Unlike the protonophore carbonyl cyanide m-chlorophenylhydrazone, which activates the mitophagy response, sorafenib treatment triggers PINK1/Parkin-dependent cellular apoptosis, which is attenuated upon Bcl-2 overexpression. In summary, our results reveal a new mechanism of action for sorafenib as a mitocan and suggest that high Parkin activity levels could make tumor cells more sensitive to sorafenib's actions, providing one possible explanation why Parkin may be a tumor suppressor gene. These insights could be useful in developing new rationally designed combination therapies with sorafenib.
AB - Sorafenib (Nexavar) is a broad-spectrum multikinase inhibitor that proves effective in treating advanced renal-cell carcinoma and liver cancer. Despite its well-characterized mechanism of action on several established cancer-related protein kinases, sorafenib causes variable responses among human tumors, although the cause for this variation is unknown. In an unbiased screening of an oncology drug library, we found that sorafenib activates recruitment of the ubiquitin E3 ligase Parkin to damaged mitochondria. We show that sorafenib inhibits the activity of both complex II/III of the electron transport chain and ATP synthase. Dual inhibition of these complexes, but not inhibition of each individual complex, stabilizes the serine-threonine protein kinase PINK1 on the mitochondrial outer membrane and activates Parkin. Unlike the protonophore carbonyl cyanide m-chlorophenylhydrazone, which activates the mitophagy response, sorafenib treatment triggers PINK1/Parkin-dependent cellular apoptosis, which is attenuated upon Bcl-2 overexpression. In summary, our results reveal a new mechanism of action for sorafenib as a mitocan and suggest that high Parkin activity levels could make tumor cells more sensitive to sorafenib's actions, providing one possible explanation why Parkin may be a tumor suppressor gene. These insights could be useful in developing new rationally designed combination therapies with sorafenib.
UR - http://www.scopus.com/inward/record.url?scp=85029222034&partnerID=8YFLogxK
U2 - 10.1074/jbc.M117.783175
DO - 10.1074/jbc.M117.783175
M3 - Article
C2 - 28673964
AN - SCOPUS:85029222034
VL - 292
SP - 15105
EP - 15120
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 36
ER -