Open AccessSmall Activating RNA Modulation of the G Protein‐Coupled Receptor for Cancer Treatment
Author(s) -
Xiong Yunfang,
Ke Ran,
Zhang Qingyu,
Lan Wenjun,
Yuan Wanjun,
Chan Karol Nga Ieng,
Roussel Tom,
Jiang Yifan,
Wu Jing,
Liu Shuai,
Wong Alice Sze Tsai,
Shim Joong Sup,
Zhang Xuanjun,
Xie Ruiyu,
Dusetti Nelson,
Iovanna Juan,
Habib Nagy,
Peng Ling,
Lee Leo Tsz On
Publication year - 2022
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202200562
Subject(s) - g protein coupled receptor , receptor , angiotensin ii , signal transduction , cancer , carcinogenesis , cancer research , biology , pharmacology , microbiology and biotechnology , chemistry , computational biology , biochemistry , genetics
G protein‐coupled receptors (GPCRs) are the most common and important drug targets. However, >70% of GPCRs are undruggable or difficult to target using conventional chemical agonists/antagonists. Small nucleic acid molecules, which can sequence‐specifically modulate any gene, offer a unique opportunity to effectively expand drug targets, especially those that are undruggable or difficult to address, such as GPCRs. Here, the authors report for the first time that small activating RNAs (saRNAs) effectively modulate a GPCR for cancer treatment. Specifically, saRNAs promoting the expression of Mas receptor (MAS1), a GPCR that counteracts the classical angiotensin II pathway in cancer cell proliferation and migration, are identified. These saRNAs, delivered by an amphiphilic dendrimer vector, enhance MAS1 expression, counteracting the angiotensin II/angiotensin II Receptor Type 1 axis, and leading to significant suppression of tumorigenesis and the inhibition of tumor progression of multiple cancers in tumor‐xenografted mouse models and patient‐derived tumor models. This study provides not only a new strategy for cancer therapy by targeting the renin‐angiotensin system, but also a new avenue to modulate GPCR signaling by RNA activation.