Page 87 - I. Chemical biology and drug discovery

A Rhenium Isonitrile Complex Induces
HSP60-mediated Mitochondrial Apoptosis.

Junhyeong Yim , and Seung Bum Park *
1
1,
1 Department of Biophysics and Chemical Biology, Seoul National University, Korea
BACKGROUND AIM
Many inorganic compounds, like Platin derivatives, are used to We are going to reveal and validate target protein of
treat cancer. Interestingly, Rhenium based compounds also Rhenium Isonitrile Complex (TRIP), and to clarify the
showed anti-cancer effect. But unlike Platinum based
compounds like Cisplatin or Carboplatin, which are DNA cross- Mechanism of Action (MoA) of TRIP against cancer
linkers, the mechanism that how Rhenium based compounds cells.
showed anti-cancer effect is still unclear.

METHODS

At first, we used ICP-MS to verify accumulation of Rhenium to proteins, not DNA. Then, we used our novel target ID
method, label-Free Target Identification Using In-Gel Fluorescence Difference via Thermal Stability Shift, called TS-
FITGE to investigate target proteins of TRIP. Validation of target proteins was conducted by Cellular Thermal Shift
Assay (CETSA), Surface Plasmon Resonance (SPR), and Knock-Down study. We also performed Western Blot to
reveal CHOP activation induced by TRIP compared to known ER stress inducer, Thapsigargin.

RESULTS

Table 1. Figure 2.
(a) (c)

Figure 1.

(a)

(b) (d)

(b)

Table 2. Figure 3.
(a) (b) (c)

(Table 1.) TRIP showed anti-cancer effect, but not to normal cells compared to Platin derivatives. (Figure 1. (b)) Also, ICP-MS data revealed
that TRIP would not work as DNA crosslinkers like Platins because Rhenium accumulates at protein, not DNA. (Figure 2. (a), Table 2.) TS-
FITGE showed target protein candidates as greenish and reddish spots. (Figure 2. (b), (c)) Heat Shock Protein 60 (HSP60) was validated as
target protein by CETSA, SPR methods. (Figure 2. (d)) Knock-Down of HSP60 at HeLa cells induces sensitization toward TRIP, and
OverExpression of HSP60 at HeLa cells induces desensitization toward TRIP. (Figure 3. (a), (b)) TRIP induce CHOP activation via JNK2
signalling, not Eif-2a signalling pathway. (Figure 3. (c)) TRIP induces mitochondrial fission.
CONCLUSION REFERENCES ACKNOWLEDGEMENTS
TRIP showed anti-cancer effect by (1) Chem. Sci., 2017, 8(2), 1127–1133. This work was supported by the Creative Research Initiative
inhibiting HSP60, which works as (2) J. Am. Chem. Soc., 2017, 139(40), 14302– Grant and the Bio & Medical Technology Development Program
through the National Research Foundation of Korea (NRF) funded
chaperonin, induces accumulation of 14314. by the Korean Government (Ministry of Science, ICT & Future
Planning). Junhyeong Yim is grateful for the Seoul National
misfolded proteins at mitochondria. University (SNU) -2020- Fostering Core Leaders of the Future
These misfolded proteins activate (3) Inorg. Chem., 2019, 58, 3895–3909. Basic Science Program/Academic Successor Generation.
CHOP via JNK2/p-JNK2 pathway. (4) ACS. Med. Chem. Lett., 2019, 10, 822–827. Contact information
CHOP activation may induce 1 Author : (E-mail) juneyim@snu.ac.kr
st
mitochondrial apoptosis of cancer (5) Chem. Eur. J., 2019, 25, 9206–9210.
cells. (6) Angew. Chem. Int. Ed., 2019, 58, 1–6. Corresponding Author : (Phone)+82-2-880-9090.
(Fax) +82-2-884-4025. (E-mail) sbpark@snu.ac.kr