Affiliation:
1. Department of Biological Sciences National University of Singapore Singapore 117543 Singapore
2. Mechanobiology Institute Singapore National University of Singapore Singapore 117411 Singapore
3. Oncovir Inc 3203 Cleveland Avenue Northwest Washington DC 20008 USA
4. NUS College National University of Singapore Singapore 138593 Singapore
5. Integrative Sciences and Engineering Programme National University of Singapore Singapore 119077 Singapore
Abstract
AbstractThe evolutionarily conserved YAP/TAZ mechanoresponsive transcription cofactors regulate development and tumorigenesis. Here, it is shown for the first time that human natural killer (NK) cells specifically express TAZ but not YAP, and TAZ serves to limit NK cytotoxicity. The synthetic double‐stranded RNA, hiltonol, is able to trigger cytoplasmic compartmentalization of TAZ, which increases NK cytotoxicity. Mechanistically, a low dose of hiltonol enhances the actin‐based intracellular contractility of NK cells accompanied by an increase in active RhoA and myosin light chain phosphorylation, conceivably through an increase in ERK1/2 activation‐dependent ROS production. Importantly, it is showed that the dissociation of LATS1 from actin upon activation of contractility is associated with TAZ cytoplasmic localization. Functionally, hiltonol also reduces the NK cell surface inhibitory receptors, e.g., KIR3DL1, through c‐Myc inhibition. Direct inhibition of c‐Myc promotes NK cytotoxicity against K562 lymphoblast. The findings are corroborated by coculturing hiltonol‐pretreated NK cells with breast and lung cancer cells, and increased NK‐mediated cancer killing is demonstrated, which conceivably occurs via compartmentalization of TAZ to the cytoplasm which facilitates NK cytotoxicity. The findings pave the way for ex vivo rejuvenation of NK cells for in vivo immunotherapies, which can involve a cocktail of low dose hiltonol and c‐Myc inhibitor.
Funder
National Research Foundation Singapore
Subject
Pharmacology (medical),Biochemistry (medical),Genetics (clinical),Pharmaceutical Science,Pharmacology,Medicine (miscellaneous)
Cited by
1 articles.
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