Sorafenib Targets the Mitochondrial Electron Transport Chain Complexes and ATP Synthase to Activate the PINK1-Parkin Pathway and Modulate Cellular Drug Response

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2017 Jul 5

PMID 28673964

Citations 46

Authors

Conggang Zhang

Zeyu Liu

Eric Bunker

Adrian Ramirez

Schuyler Lee

Yinghua Peng

Aik-Choon Tan

S Gail Eckhardt

Douglas A Chapnick

Xuedong Liu

Affiliations

Soon will be listed here.

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 -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.

Citing Articles

Mitochondrial abnormalities as a target of intervention in acute myeloid leukemia.

Tjahjono E, Daneman M, Meika B, Revtovich A, Kirienko N Front Oncol. 2025; 14:1532857.

PMID: 39902131 PMC: 11788353. DOI: 10.3389/fonc.2024.1532857.

The bioenergetic landscape of cancer.

Zunica E, Axelrod C, Gilmore L, Gnaiger E, Kirwan J Mol Metab. 2024; 86:101966.

PMID: 38876266 PMC: 11259816. DOI: 10.1016/j.molmet.2024.101966.

Signaling pathways in liver cancer: pathogenesis and targeted therapy.

Xue Y, Ruan Y, Wang Y, Xiao P, Xu J Mol Biomed. 2024; 5(1):20.

PMID: 38816668 PMC: 11139849. DOI: 10.1186/s43556-024-00184-0.

Strobilurin X acts as an anticancer drug by inhibiting protein synthesis and suppressing mitochondrial respiratory chain activity.

Takahashi K, Tanaka T, Ishihara A, Ohta T Discov Oncol. 2024; 15(1):177.

PMID: 38769217 PMC: 11106052. DOI: 10.1007/s12672-024-01041-w.

Cloflucarban Illuminates Specificity and Context-Dependent Activation of the PINK1-Parkin Pathway by Mitochondrial Complex Inhibition.

Ramirez A, Liu Z, Xu Q, Nowosadtko S, Liu X Biomolecules. 2024; 14(3).

PMID: 38540668 PMC: 10967832. DOI: 10.3390/biom14030248.

References

Wilhelm S, Carter C, Tang L, Wilkie D, McNabola A, Rong H . BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004; 64(19):7099-109. DOI: 10.1158/0008-5472.CAN-04-1443. View

Bull V, Rajalingam K, Thiede B . Sorafenib-induced mitochondrial complex I inactivation and cell death in human neuroblastoma cells. J Proteome Res. 2012; 11(3):1609-20. DOI: 10.1021/pr200790e. View

Yoshii S, Kishi C, Ishihara N, Mizushima N . Parkin mediates proteasome-dependent protein degradation and rupture of the outer mitochondrial membrane. J Biol Chem. 2011; 286(22):19630-40. PMC: 3103342. DOI: 10.1074/jbc.M110.209338. View

Picchio M, Martin E, Cesari R, Calin G, Yendamuri S, Kuroki T . Alterations of the tumor suppressor gene Parkin in non-small cell lung cancer. Clin Cancer Res. 2004; 10(8):2720-4. DOI: 10.1158/1078-0432.ccr-03-0086. View

Veeriah S, Taylor B, Meng S, Fang F, Yilmaz E, Vivanco I . Somatic mutations of the Parkinson's disease-associated gene PARK2 in glioblastoma and other human malignancies. Nat Genet. 2009; 42(1):77-82. PMC: 4002225. DOI: 10.1038/ng.491. View

Sawyers C . Targeted cancer therapy. Nature. 2004; 432(7015):294-7. DOI: 10.1038/nature03095. View

Yu C, Bruzek L, Meng X, Gores G, Carter C, Kaufmann S . The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43-9006. Oncogene. 2005; 24(46):6861-9. DOI: 10.1038/sj.onc.1208841. View

Sutherland G, Richards R . The molecular basis of fragile sites in human chromosomes. Curr Opin Genet Dev. 1995; 5(3):323-7. DOI: 10.1016/0959-437x(95)80046-8. View

Poulogiannis G, McIntyre R, Dimitriadi M, Apps J, Wilson C, Ichimura K . PARK2 deletions occur frequently in sporadic colorectal cancer and accelerate adenoma development in Apc mutant mice. Proc Natl Acad Sci U S A. 2010; 107(34):15145-50. PMC: 2930574. DOI: 10.1073/pnas.1009941107. View

10.

Carroll R, Hollville E, Martin S . Parkin sensitizes toward apoptosis induced by mitochondrial depolarization through promoting degradation of Mcl-1. Cell Rep. 2014; 9(4):1538-53. DOI: 10.1016/j.celrep.2014.10.046. View

11.

Fujiwara M, Marusawa H, Wang H, Iwai A, Ikeuchi K, Imai Y . Parkin as a tumor suppressor gene for hepatocellular carcinoma. Oncogene. 2008; 27(46):6002-11. DOI: 10.1038/onc.2008.199. View

12.

Wang F, Denison S, Lai J, Philips L, Montoya D, Kock N . Parkin gene alterations in hepatocellular carcinoma. Genes Chromosomes Cancer. 2004; 40(2):85-96. DOI: 10.1002/gcc.20020. View

13.

Zhang C, Lee S, Peng Y, Bunker E, Giaime E, Shen J . PINK1 triggers autocatalytic activation of Parkin to specify cell fate decisions. Curr Biol. 2014; 24(16):1854-65. PMC: 4143385. DOI: 10.1016/j.cub.2014.07.014. View

14.

Gautier C, Kitada T, Shen J . Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress. Proc Natl Acad Sci U S A. 2008; 105(32):11364-9. PMC: 2516271. DOI: 10.1073/pnas.0802076105. View

15.

Prieto-Dominguez N, Ordonez R, Fernandez A, Mendez-Blanco C, Baulies A, Garcia-Ruiz C . Melatonin-induced increase in sensitivity of human hepatocellular carcinoma cells to sorafenib is associated with reactive oxygen species production and mitophagy. J Pineal Res. 2016; 61(3):396-407. PMC: 5018464. DOI: 10.1111/jpi.12358. View

16.

Cabanillas M, Waguespack S, Bronstein Y, Williams M, Feng L, Hernandez M . Treatment with tyrosine kinase inhibitors for patients with differentiated thyroid cancer: the M. D. Anderson experience. J Clin Endocrinol Metab. 2010; 95(6):2588-95. DOI: 10.1210/jc.2009-1923. View

17.

McLelland G, Soubannier V, Chen C, McBride H, Fon E . Parkin and PINK1 function in a vesicular trafficking pathway regulating mitochondrial quality control. EMBO J. 2014; 33(4):282-95. PMC: 3989637. DOI: 10.1002/embj.201385902. View

18.

Sarraf S, Raman M, Guarani-Pereira V, Sowa M, Huttlin E, Gygi S . Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization. Nature. 2013; 496(7445):372-6. PMC: 3641819. DOI: 10.1038/nature12043. View

19.

Youle R, Narendra D . Mechanisms of mitophagy. Nat Rev Mol Cell Biol. 2010; 12(1):9-14. PMC: 4780047. DOI: 10.1038/nrm3028. View

20.

Spencer S, Gaudet S, Albeck J, Burke J, Sorger P . Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis. Nature. 2009; 459(7245):428-32. PMC: 2858974. DOI: 10.1038/nature08012. View