Tetrathiomolybdate , kuparia sitova aine, Cisplatin- resistenssin kierto

https://www.ncbi.nlm.nih.gov/pubmed/?term=tetrathiomolybdate

Nat Commun. 2019 Jan 14;10(1):186. doi: 10.1038/s41467-018-08102-z.

Tetrathiomolybdate induces dimerization of the metal-binding domain of ATPase and inhibits platination of the protein.

Fang T¹, Chen W², Sheng Y¹, Yuan S¹, Tang Q³, Li G¹, Huang G¹, Su J³, Zhang X⁴, Zang J⁵, Liu Y⁶.

Author information

Abstract

Tetrathiomolybdate (TM) is used in the clinic for the treatment of Wilson's disease by targeting the cellular copper efflux protein ATP7B (WLN). Interestingly, both TM and WLN are associated with the efficacy of cisplatin, a widely used anticancer drug. Herein, we show that TM induces dimerization of the metal-binding domain of ATP7B (WLN4) through a unique sulfur-bridged Mo₂S₆O₂ cluster. TM expels copper ions from Cu-WLN4 and forms a copper-free dimer. The binding of Mo to cysteine residues of WLN4 inhibits platination of the protein. Reaction with multi-domain proteins indicates that TM can also connect two domains in the same molecule, forming Mo-bridged intramolecular crosslinks. These results provide structural and chemical insight into the mechanism of action of TM against ATPase, and reveal the molecular mechanism by which TM attenuates the cisplatin resistance mediated by copper efflux proteins.

PMID:

30643139

PMCID:

PMC6331642

DOI:

10.1038/s41467-018-08102-z

Free PMC Article Introduction

P-type ATPases, including ATP7A and ATP7B, are responsible for active copper efflux that is essential for maintaining copper homeostasis in mammalian cells¹. These two proteins are also known as Menkes (MNK) and Wilson (WLN) disease proteins, since dysfunction of ATP7A and ATP7B leads to these diseases, respectively. Interestingly, these Cu-ATPases are also associated with resistance to cisplatin, one of the most widely used anticancer drugs in the clinic^2,3. Overexpression of Cu-ATPases is a feature of cisplatin-resistant cancer cells^3–6, while silencing of Cu-ATPase genes recovers drug sensitivity⁷. Mechanistic studies revealed that Cu-ATPases are involved in the efflux/sequestration of cisplatin^2,6. 

ATPases contain six metal-binding domains (MBDs) that share high sequence homology with Atox1, a chaperone delivering copper to ATPase, and exhibit similar copper-binding properties⁸.

 Cisplatin can directly bind to the MBDs of ATPases at the Cu-binding site, and MBDs are required to modulate resistance to cisplatin^9,10. These findings suggest that the inhibition of cisplatin binding to the MBDs of ATPases could be an effective approach to circumvent drug resistance of cisplatin.