Tobramycin suppresses HUWE1 degradation to control MCL-1 stability during tumour development.

Tobramycin suppresses HUWE1 degradation to control MCL-1 stability during tumour development. Clin Exp Pharmacol Physiol. 2020 May 07;: Authors: Jiabei H, Sixian W, Li X, Li T, Hanxiao C, Lang Q, Jiang X, Tao L, Wenming X Abstract HUWE1 is an E3 ubiquitin ligase that is involved in cancer cell proliferation by regulating MCL-1 stability. The HECT domain has been shown to be required for the ubiquitin ligase activity of HUWE1. To identify efficient drugs that impairthe activity of HUWE1, and thus decrease MCL-1 accumulation, we screened 2000 candidate compounds that might suppress HUWE1 activity. To evaluate these 2000 candidates, the HECT domain of HUWE1, which is the catalytic domain responsible for MCL1 ubiquitination, was selected as a conjugation site, and putative binding candidates were filtrated. Tobramycin emerged as one of the compounds that show efficient binding ability with the HECT domain of HUWE1. The surface plasmon resonance (SPR) results validated the specific binding of Tobramycin with the HECT domain. Subsequent analyses demonstrated its potential to inhibit cancer cell proliferation by binding to the HECT domain of HUWE1 and impeding the HUWE1-mediated ubiquitination of MCL-1. Consequently, the accumulation of MCL-1 inhibited the proliferation of tumour cells, while the apoptosis rates were not significantly altered after Tobramycin treatment. In vitro experiments showed that Tobramycin could inhibit cell prolifer...
Source: Clinical and Experimental Pharmacology and Physiology - Category: Drugs & Pharmacology Authors: Tags: Clin Exp Pharmacol Physiol Source Type: research