Abstract
Elucidation of the molecular mechanism of therapeutic agents and potential candidates is in high demand. Interestingly, rhenium-based complexes have shown a highly selective anticancer effect, only on cancer cells, unlike platinum-based drugs, such as cisplatin and carboplatin. These differences might be attributed to their different molecular targets. We confirmed that the target of tricarbonyl rhenium isonitrile polypyridyl (TRIP) complex is a protein, not DNA, using ICP-MS analysis and identified heat shock protein 60 (HSP60) as its target protein using a label-free target identification method. The subsequent biological evaluation revealed that TRIP directly inhibits the chaperone function of HSP60 and induces the accumulation of misfolded proteins in mitochondria, thereby leading to the activation of mitochondrial unfolded protein response (mtUPR)-mediated JNK2/AP-1/CHOP apoptotic pathway.
Highlights
Cancer, the uncontrolled growth of cells, is the second leading cause of death in the United States (Shewach and Kuchta, 2009; Siegel et al, 2021)
Another study showed that oxaliplatin and some derivatives induce nucleolar stress derived from their organic ligands (Sutton et al, 2019), which means that the ligands of platinum-based complexes could alter their target proteins and modes of action
Among the potential target proteins identified from these spots, we focused on heat shock protein 60 (HSP60) (Bukau and Horwich, 1998), a mitochondrial chaperone protein, since we knew that tricarbonyl rhenium isonitrile polypyridyl (TRIP) treatment causes changes in mitochondrial morphology (King et al, 2019)
Summary
The uncontrolled growth of cells, is the second leading cause of death in the United States (Shewach and Kuchta, 2009; Siegel et al, 2021). Another study showed that oxaliplatin and some derivatives induce nucleolar stress derived from their organic ligands (Sutton et al, 2019), which means that the ligands of platinum-based complexes could alter their target proteins and modes of action These events were observed in nonplatinum-based anticancer agents. Developed rhenium-based compounds have shown anticancer effects (Knopf et al, 2017) Wilson and his co-workers produced various rhenium analogs via combinatorial synthesis and selected TRIP as a therapeutic candidate with improved anticancer efficacy (Konkankit et al, 2019a; Konkankit et al, 2019b; King et al, 2019). Even though there are high demands to reveal the exact molecular target of TRIP, the application of conventional target identification methods with affinity-based probes is quite limited since the structural modification of organic ligands in rhenium-based complexes might hamper the activity of its probes or alter the engagement pattern to their targets (Bregman et al, 2006; Feng et al, 2011). We revealed the molecular mechanism underlying the cytotoxicity of TRIP
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
