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Theranostics 2023; 13(13):4333-4355. doi:10.7150/thno.85421 This issue Cite

Research Paper

Kindlin-2 enhances c-Myc translation through association with DDX3X to promote pancreatic ductal adenocarcinoma progression

Chengmin Liu1, Ke Jiang1, Yanyan Ding1, Aihua Yang1, Renwei Cai1, Panzhu Bai1, Minggang Xiong2, Changying Fu3, Meiling Quan1, Zailin Xiong1, Yi Deng1, Ruijun Tian3,5, Chuanyue Wu4✉, Ying Sun1,5✉

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 and University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15260, USA.
5. Research Center for Chemical Biology and Omics Analysis, College of Science, Southern University of Science and Technology, Shenzhen, 518055, China.

✉ Corresponding author: C.W. (email: carywuedu) or Y.S. (email: sunyedu.cn).

Citation:
Liu C, Jiang K, Ding Y, Yang A, Cai R, Bai P, Xiong M, Fu C, Quan M, Xiong Z, Deng Y, Tian R, Wu C, Sun Y. Kindlin-2 enhances c-Myc translation through association with DDX3X to promote pancreatic ductal adenocarcinoma progression. Theranostics 2023; 13(13):4333-4355. doi:10.7150/thno.85421. https://www.thno.org/v13p4333.htm
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Abstract

Graphic abstract

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 KrasG12D-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.

Keywords: Kindlin-2, DDX3X, c-Myc, Pancreatic ductal adenocarcinoma, translation

Citation styles

APA
Liu, C., Jiang, K., Ding, Y., Yang, A., Cai, R., Bai, P., Xiong, M., Fu, C., Quan, M., Xiong, Z., Deng, Y., Tian, R., Wu, C., Sun, Y. (2023). Kindlin-2 enhances c-Myc translation through association with DDX3X to promote pancreatic ductal adenocarcinoma progression. Theranostics, 13(13), 4333-4355. https://doi.org/10.7150/thno.85421.

ACS
Liu, C.; Jiang, K.; Ding, Y.; Yang, A.; Cai, R.; Bai, P.; Xiong, M.; Fu, C.; Quan, M.; Xiong, Z.; Deng, Y.; Tian, R.; Wu, C.; Sun, Y. Kindlin-2 enhances c-Myc translation through association with DDX3X to promote pancreatic ductal adenocarcinoma progression. Theranostics 2023, 13 (13), 4333-4355. DOI: 10.7150/thno.85421.

NLM
Liu C, Jiang K, Ding Y, Yang A, Cai R, Bai P, Xiong M, Fu C, Quan M, Xiong Z, Deng Y, Tian R, Wu C, Sun Y. Kindlin-2 enhances c-Myc translation through association with DDX3X to promote pancreatic ductal adenocarcinoma progression. Theranostics 2023; 13(13):4333-4355. doi:10.7150/thno.85421. https://www.thno.org/v13p4333.htm

CSE
Liu C, Jiang K, Ding Y, Yang A, Cai R, Bai P, Xiong M, Fu C, Quan M, Xiong Z, Deng Y, Tian R, Wu C, Sun Y. 2023. Kindlin-2 enhances c-Myc translation through association with DDX3X to promote pancreatic ductal adenocarcinoma progression. Theranostics. 13(13):4333-4355.

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