N-end rule pathway inhibitor sensitizes cancer cells to antineoplastic agents by regulating XIAP and RAD21 protein expression

N-end rule pathway inhibitor sensitizes cancer cells to antineoplastic agents by regulating XIAP and RAD21 protein expression

Pore Subrata K; Ganguly Anirban; Sau Samaresh; Godeshala Sudhakar; Kanugula Anantha K; Ummanni Ramesh; Kotamraju Srigiridhar; Banerjee Rajkumar

Journal of Cellular Biochemistry

2019

2019-08

Anticancer drugs exert their effects on cancer cells by deregulating many pathways linked to cell cycle, apoptosis, etc. but cancer cells gradually become resistive against anticancer drugs, thereby necessitating the development of newer generation anticancer molecules. N-end rule pathway has been shown to be involved in the degradation of many cell cycle and apoptosis-related proteins. However, the involvements of this pathway in cancer are not well established. Recently, we developed a non-peptide-based N-end rule pathway inhibitor, RF-C11 for type 1 and 2 recognition domains of E3 ubiquitin ligases. The inhibitor significantly increased the half-life of potential N-degrons leading to significant physiological changes in vivo. We hypothesized RF-C11 may be used to decipher the N-end rule pathway's role in cancer towards the development of anticancer therapeutics. In this study, we showed that RF-C11, barring noncancer cells, significantly sensitizes cancer cells towards different anticancer agents tested. We further find that the profound cellular sensitization to anticancer drugs was affected by (a) downregulation of X-linked inhibitor of apoptosis protein, an antiapoptotic protein and (b) by stabilization of RAD21, and thereby inhibiting metaphase to anaphase promotion. The study shows that RF-C11 or its analogs may be used as a novel additive in combination therapy against cancer.

apoptosis; Biochemistry & Molecular Biology; cancer; Cell Biology; cleavage; cyclin; degradation; drug sensitivity; hdm2; heterovalent inhibitors; mechanisms; N-end rule; oncoprotein; RAD21; reaper; substrate; UBR1; XIAP

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).