USP1 deubikitinasa pankrea-minbiziaren aurkako itu terapeutiko gisa

Abstract

Ubikitinazio-deubikitinazio prozesuen arteko oreka ezinbestekoa da zelularen ingurunea osasuntsu mantentzeko. Oreka honetan deubikitinasak oso garrantzitsuak dira. Izan ere, oreka honen erregulazioaren galera hainbat gaixotasunekin erlazionatu da, hauen artean minbizia. Hori dela eta, USP1 giza deubikitinasa oso erakargarria da minbiziaren kontrako itu terapeutiko moduan, DNA-kaltearen aurkako erantzunean jokatzen duen paper kritikoarengatik. USP1en inhibitzailea den ML323 konposatuak biriketako minbizian garatzen den zisplatinoarekiko erresistentzia gainditzen duela erakutsi da. Dena den, USP1ek beste minbizi motetan jokatzen duen papera guztiz ezezaguna da. Ikerketa honetan, USP1ek pankrea-minbiziari aurre egiteko itu terapeutiko gisa duen ahalmena aztertzen da.

The dynamic balance between ubiquitination and deubiquitination determines the final ubiquitination status of the substrate, ensuring a healthy cellular homeostasis. Deubiquitinases are important in this balance. Thus, dysregulations in the ubiquitination-deubiquitination machinery are highly related to human diseases, particularly tumor development. In this regard, targeting human deubiquitinase USP1, a known regulator of the DNA damage response (DDR) may constitute a promising anticancer target to improve the efficacy of the conventional drugs. ML323, the most specific USP1 inhibitor to date, was shown to reverse the resistance of non-small cell lung cancer (NSCLC) cells to the conventional therapeutic agent cisplatin. Nevertheless, there is no information to date about the potential effects of USP1 in other cancer types. In an attempt to extend these findings to other cancer types, we aimed to analyze the potential of USP1 as a novel target in pancreatic cancer.