Antibiotic heliomycin and its water-soluble 4-aminomethylated derivative provoke cell death in T24 bladder cancer cells by targeting sirtuin 1 (SIRT1)

Ming Hung Lin; Atikul Islam; Yen-Hui Liu; Chia-Wei Weng; Jun-Han Zhan; Ru-Hao Liang; Alexander S Tikhomirov; Andrey E Shchekotikhin; Pin Ju Chueh

Antibiotic heliomycin and its water-soluble 4-aminomethylated derivative provoke cell death in T24 bladder cancer cells by targeting sirtuin 1 (SIRT1)

Am J Cancer Res. 2022 Mar 15;12(3):1042-1055. eCollection 2022.

Authors

Ming Hung Lin^{1

2}, Atikul Islam³, Yen-Hui Liu³, Chia-Wei Weng^{3

4}, Jun-Han Zhan³, Ru-Hao Liang³, Alexander S Tikhomirov⁵, Andrey E Shchekotikhin⁵, Pin Ju Chueh^{3

6

7}

Affiliations

¹ Division of Urology, Department of Surgery, An Nan Hospital, China Medical University Tainan 70965, Taiwan.
² Division of Urology, Department of Surgery, Tri-service General Hospital Taipei 11490, Taiwan.
³ Institute of Biomedical Sciences, National Chung Hsing University Taichung 40227, Taiwan.
⁴ Institute of Medicine, Chung Shan Medical University Taichung 40201, Taiwan.
⁵ Gause Institute of New Antibiotics 11 B. Pirogovskaya Street, Moscow 119021, Russia.
⁶ Department of Medical Research, China Medical University Hospital Taichung 40402, Taiwan.
⁷ Graduate Institute of Basic Medicine, China Medical University Taichung 40402, Taiwan.

PMID: 35411221
PMCID: PMC8984893

Abstract

Bladder cancer is one of the most frequent cancers among males, and a poor survival rate reflects problems with aggressiveness and chemo-resistance. Accumulating evidence indicates that SIRT1 is involved in bladder cancer tumorigenesis and is positively associated with chemo-resistance and poor prognosis. We recently synthesized water-soluble chemical derivatives of heliomycin, an antibiotic from Streptomyces resistomycificus, and demonstrated that they possess anticancer properties. In this present study, we used the cellular thermal shift assay (CETSA) in T24 bladder cancer cells to show that heliomycin (designated compound (H1)) and its 4-(tert-butylamino)methyl derivative (HD2) directly engaged with SIRT1 in the native cellular environment, whereas another derivative (HD3) did not. Upon binding, heliomycin downregulated SIRT1 protein expression without altering its transcript level, and subsequently induced autophagy. Interestingly, the derivative (HD2) triggered apoptosis. The interaction between SIRT1 protein and heliomycin or its derivatives was also speculated by a molecular docking simulation, suggesting heliomycin (H1) and derivative (HD2) acting with the different binding modes to SIRT1. Given the increased water-solubility, hydrogen bonds were found on Ala262 and Ile347 residues in the docked complex of derivative (HD2) to produce more steady interaction and initiate signaling pathways that were not observed in the case of heliomycin. Meanwhile, it is evident that derivative (HD3) did not engage with SIRT1 by CETSA or molecular docking studies, nor did it downregulate SIRT1 expression. Taken together, these findings clearly show that SIRT1 is targeted and downregulated by heliomycin and its water-soluble 4-aminomethylated derivative (HD2) possibly through autophagic and/or proteasomal degradation, leading to cell death and growth suppression of T24 bladder cancer cells.

Keywords: Apoptosis; autophagy; bladder cancer; cellular thermal shift assay; heliomycin; resistomycin; silent mating type information regulation 1 (Sirtuin 1, SIRT1).