Label-Free Target Identification Reveals the Anticancer Mechanism of a Rhenium Isonitrile Complex

Junhyeong Yim; Seung Bum Park

doi:10.3389/fchem.2022.850638

Label-Free Target Identification Reveals the Anticancer Mechanism of a Rhenium Isonitrile Complex

Front Chem. 2022 Mar 14:10:850638. doi: 10.3389/fchem.2022.850638. eCollection 2022.

Authors

Junhyeong Yim¹, Seung Bum Park^{1

2}

Affiliations

¹ Department of Biophysics and Chemical Biology, Seoul National University, Seoul, South Korea.
² CRI Center for Chemical Proteomics, Department of Chemistry, Seoul National University, Seoul, South Korea.

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.

Keywords: anticancer agents; heat shock protein 60; label-free target identification; metal-based drug; rhenium isonitrile complex.