Format

Send to

Choose Destination
J Biol Chem. 2017 Sep 8;292(36):15105-15120. doi: 10.1074/jbc.M117.783175. Epub 2017 Jul 3.

Sorafenib targets the mitochondrial electron transport chain complexes and ATP synthase to activate the PINK1-Parkin pathway and modulate cellular drug response.

Author information

1
From the Department of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, Colorado 80303 and.
2
the Developmental Therapeutics Program, Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045.
3
From the Department of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, Colorado 80303 and Xuedong.Liu@colorado.edu.

Abstract

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.

KEYWORDS:

PTEN-induced putative kinase 1 (PINK1); apoptosis; mitochondria; mitophagy; parkin

PMID:
28673964
PMCID:
PMC5592685
DOI:
10.1074/jbc.M117.783175
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center