Kindlin-2 enhances c-Myc translation through association with DDX3X to promote pancreatic ductal adenocarcinoma progression
|Corresponding Author||Wu，Chuanyue; Sun，Ying|
Rationale: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive solid tumor, with extremely low survival rates. Identifying key signaling pathways driving PDAC progression is crucial for the development of therapies to improve patient response rates. Kindlin-2, a multi-functional protein, is involved in numerous biological processes including cell proliferation, apoptosis and migration. However, little is known about the functions of Kindlin-2 in pancreatic cancer progression in vivo. Methods: In this study, we employ an in vivo PDAC mouse model to directly investigate the role of Kindlin-2 in PDAC progression. Then, we utilized RNA-sequencing, the molecular and cellular assays to determine the molecular mechanisms by which Kindlin-2 promotes PDAC progression. Results: We show that loss of Kindlin-2 markedly inhibits Kras-driven pancreatic cancer progression in vivo as well as in vitro. Furthermore, we provide new mechanistic insight into how Kindlin-2 functions in this process, A fraction of Kindlin-2 was localized to the endoplasmic reticulum and associated with the RNA helicase DDX3X, a key regulator of mRNA translation. Loss of Kindlin-2 blocked DDX3X from binding to the 5’-untranslated region of c-Myc and inhibited DDX3X-mediated c-Myc translation, leading to reduced c-Myc-mediated glucose metabolism and tumor growth. Importantly, restoration of the expression of either the full-length Kindlin-2 or c-Myc, but not that of a DDX3X-binding-defective mutant of Kindlin-2, in Kindlin-2 deficient PDAC cells, reversed the inhibition of glycolysis and pancreatic cancer progression induced by the loss of Kindlin-2. Conclusion: Our studies reveal a novel Kindlin-2-DDX3X-c-Myc signaling axis in PDAC progression and suggest that inhibition of this signaling axis may provide a promising therapeutic approach to alleviate PDAC progression.
First ; Corresponding
Natural Science Foundation of Guangdong Province[2017B030 301018] ; Shenzhen Graduate School, Peking University ; Natural Science Foundation of Guangdong Province[2121B1515120063] ; National Natural Science Foundation of China ; Shenzhen Graduate School, Peking University[GXWD20201230110313001] ; Science, Technology and Innovation Commission of Shenzhen Municipality[JCYJ20190809 141003834] ; Science, Technology and Innovation Commission of Shenzhen Municipality[JCYJ20200109141212325]
|WOS Research Area|
Research & Experimental Medicine
Medicine, Research & Experimental
|WOS Accession No|
Cited Times [WOS]:0
|Document Type||Journal Article|
|Department||School of Medicine|
1.Department of System Biology,School of Life Sciences,Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research,Shenzhen Key Laboratory of Cell Microenvironment,Southern University of Science and Technology,Shenzhen,518055,China
2.Department of Human Cell Biology and Genetics,School of Medicine,Southern University of Science and Technology,Shenzhen,518055,China
3.Department of Chemistry,Southern University of Science and Technology,Shenzhen,518055,China
4.Department of Pathology,School of Medicine,University of Pittsburgh Cancer Institute,University of Pittsburgh,Pittsburgh,15260,United States
5.Research Center for Chemical Biology and Omics Analysis,College of Science,Southern University of Science and Technology,Shenzhen,518055,China
|First Author Affilication||School of Medicine; School of Life Sciences|
|Corresponding Author Affilication||School of Medicine; School of Life Sciences; College of Science|
|First Author's First Affilication||School of Medicine; School of Life Sciences|
Liu，Chengmin,Jiang，Ke,Ding，Yanyan,et al. Kindlin-2 enhances c-Myc translation through association with DDX3X to promote pancreatic ductal adenocarcinoma progression[J]. Theranostics,2023,13(13):4333-4355.
Liu，Chengmin.,Jiang，Ke.,Ding，Yanyan.,Yang，Aihua.,Cai，Renwei.,...&Sun，Ying.(2023).Kindlin-2 enhances c-Myc translation through association with DDX3X to promote pancreatic ductal adenocarcinoma progression.Theranostics,13(13),4333-4355.
Liu，Chengmin,et al."Kindlin-2 enhances c-Myc translation through association with DDX3X to promote pancreatic ductal adenocarcinoma progression".Theranostics 13.13(2023):4333-4355.
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