Serine-arginine protein kinase 1 (SRPK1) promotes EGFR-TKI resistance by enhancing GSK3β Ser9 autophosphorylation independent of its kinase activity in non-small-cell lung cancer

Huang，Jing Qiang1,2,3; Duan，Ling Xin1,4; Liu，Qiu Yu5; Li，He Feng1,3; Hu，Ao Ping1; Song，Jun Wei1,6; Lin，Chuxuan7; Huang，Bingsheng7; Yao，Da8; Peng，Bin2; Sun，Yehong9; Wen，Yuxin10; Yang，Lin10; Xu，Xingzhi2; Gong，Li Yun1

2023-04-06

10.1038/s41388-023-02645-2

Oncogene   Impact Factor & Quartile

0950-9232

1476-5594

Resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is a major challenge for clinicians and patients with non-small cell lung cancer (NSCLC). Serine-arginine protein kinase 1 (SRPK1) is a key oncoprotein in the EGFR/AKT pathway that participates in tumorigenesis. We found that high SRPK1 expression was significantly associated with poor progression-free survival (PFS) in patients with advanced NSCLC undergoing gefitinib treatment. Both in vitro and in vivo assays suggested that SRPK1 reduced the ability of gefitinib to induce apoptosis in sensitive NSCLC cells independently of its kinase activity. Moreover, SRPK1 facilitated binding between LEF1, β-catenin and the EGFR promoter region to increase EGFR expression and promote the accumulation and phosphorylation of membrane EGFR. Furthermore, we verified that the SRPK1 spacer domain bound to GSK3β and enhanced its autophosphorylation at Ser9 to activate the Wnt pathway, thereby promoting the expression of Wnt target genes such as Bcl-X. The correlation between SRPK1 and EGFR expression was confirmed in patients. In brief, our research suggested that the SRPK1/GSK3β axis promotes gefitinib resistance by activating the Wnt pathway and may serve as a potential therapeutic target for overcoming gefitinib resistance in NSCLC. [Figure not available: see fulltext.]

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Natural Science Foundation of Henan Province[202300410384];National Natural Science Foundation of China-Yunnan Joint Fund[82003789];

WOS:000943347000001

MOLECULAR BIOLOGY & GENETICS

2-s2.0-85149257216

Scopus

1.Guangdong Provincial Key Laboratory for Genome Stability and Disease Prevention,Department of Biochemistry and Molecular Biology,School of Basic Medical Sciences,Shenzhen University Medical School,Shenzhen,Guangdong,518055,China
2.Guangdong Provincial Key Laboratory for Genome Stability and Disease Prevention,Carson International Cancer Center,and Marshall Laboratory of Biomedical Engineering,Shenzhen University Medical School,Shenzhen,Guangdong,518055,China
3.School of Biomedical Engineering,Shenzhen University Medical School,Shenzhen,Guangdong,518055,China
4.School of Pharmaceutical Sciences,Shenzhen University Medical School,Shenzhen,Guangdong,518055,China
5.Department of Pathology,Henan Provincial People’s Hospital,The People’s Hospital of Zhengzhou University,Zhengzhou,Henan,450003,China
6.Medical School,Southern University of Science and Technology,Shenzhen,Guangdong,518005,China
7.Medical AI Lab,School of Biomedical Engineering,Shenzhen University Medical School,Shenzhen,Guangdong,518055,China
8.Department of Thoracic Surgery,The First Affiliated Hospital of Shenzhen University,Shenzhen Second People’s Hospital,Shenzhen,China
9.Department of Clinical Pharmacy,Shenzhen Traditional Chinese Medicine Hospital,4th Clinical Medical College of Guangzhou University of Chinese Medicine,Shenzhen,Guangdong,518005,China
10.Department of Thoracic Surgery,Shenzhen People’s Hospital,2nd Clinical Medical College of Jinan University,Shenzhen,Guangdong,518020,China

Huang，Jing Qiang,Duan，Ling Xin,Liu，Qiu Yu,et al. Serine-arginine protein kinase 1 (SRPK1) promotes EGFR-TKI resistance by enhancing GSK3β Ser9 autophosphorylation independent of its kinase activity in non-small-cell lung cancer[J]. Oncogene,2023,42(15):1233-1246.

Huang，Jing Qiang.,Duan，Ling Xin.,Liu，Qiu Yu.,Li，He Feng.,Hu，Ao Ping.,...&Gong，Li Yun.(2023).Serine-arginine protein kinase 1 (SRPK1) promotes EGFR-TKI resistance by enhancing GSK3β Ser9 autophosphorylation independent of its kinase activity in non-small-cell lung cancer.Oncogene,42(15),1233-1246.

Huang，Jing Qiang,et al."Serine-arginine protein kinase 1 (SRPK1) promotes EGFR-TKI resistance by enhancing GSK3β Ser9 autophosphorylation independent of its kinase activity in non-small-cell lung cancer".Oncogene 42.15(2023):1233-1246.