Pharmacological targeting PTK6 inhibits the JAK2/STAT3 sustained stemness and reverses chemoresistance of colorectal cancer

Chaoqun Liu,Liang Zhao,Ling Wu,Qian Chen,Weiwei Liu,Yujie Zhang,Wandie Lin,Muhong Jiang,Weihao Lin,Zhihua Pan,Rui Zhou,Zetao Chen

doi:10.1186/s13046-021-02059-6

Abstract

BackgroundChemoresistance is the major cause of chemotherapy failure in patients with colorectal cancer (CRC). Protein tyrosine kinase 6 (PTK6) is aberrantly overexpressed in clinical CRC tissues undergoing chemotherapy. We studied if PTK6 contributed to the chemoresistance of CRC in human and mice.MethodsWe obtained tissue samples from patients with CRC and measured the expression of PTK6 by immunohistochemistry. Gain- and loss-of-function assays were performed to study the biological functions of PTK6. We constructed the FLAG-tagged wild type (WT), kinase-dead, and inhibition-defective recombinant mutants of PTK6 to study the effect phosphorylated activation of PTK6 played on CRC cell stemness and chemoresistance. We used small molecule inhibitor XMU-MP-2 to test the influence of PTK6 on sensitivity of CRC cells to 5-FU/L-OHP in both nude mouse and patient-derived xenograft (PDX) animal models.ResultsPTK6 is overexpressed in CRC tissues and plays a stimulatory role in the proliferation and chemoresistance of CRC cells both in vitro and in vivo. PTK6, especially the phosphorylated PTK6, can promote the stemness of CRC cells through interacting with JAK2 and phosphorylating it to activate the JAK2/STAT3 signaling. Pharmacological inhibition of PTK6 using XMU-MP-2 effectively reduces the stemness property of CRC cells and improves its chemosensitivity to 5-FU/L-OHP in both nude mice subcutaneously implanted tumor model and PDX model constructed with NOD-SCID mice.ConclusionsPTK6 interacts with JAK2 and phosphorylates it to activate JAK2/STAT3 signaling to promote the stemness and chemoresistance of CRC cells. Pharmacological inhibition of PTK6 by small molecule inhibitor dramatically enhances the sensitivity to chemotherapy in nude mice and PDX models.

Highlights

Chemoresistance is the major cause of chemotherapy failure in patients with colorectal cancer (CRC)
Overexpression of Protein tyrosine kinase 6 (PTK6) is associated with the malignant progression of CRC To investigate the role of PTK6 in CRC progression, we examined the expression of PTK6 in public microarray
We knocked down the endogenous expression of PTK6 in HCT116 and SW620 cells by introducing two short hairpin RNAs, which were named as sh1PTK6 and sh2-PTK6

Summary

Introduction

Chemoresistance is the major cause of chemotherapy failure in patients with colorectal cancer (CRC). Protein tyrosine kinase 6 (PTK6) is aberrantly overexpressed in clinical CRC tissues undergoing chemotherapy. Surgical resection and chemotherapy are two major treatments for CRC [2]. Chemotherapy can palliate symptoms and prolong life of advanced CRC patients, but it fails to dramatically improve the clinical outcomes of patients with recurrent or metastatic chemoresistant CRC [3,4,5]. A better understanding of molecular mechanisms underlying chemoresistance is essential for us to develop effective therapeutic strategies against CRC. Since tyrosine kinases could participate in the regulation of many different signaling pathways [10, 11],the dysfunction of PTK6 often lead to the development and progression of tumors [8]

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