SRPK1/AKT axis promotes oxaliplatin-induced anti-apoptosis via NF-\u03baB activation in colon cancer

Jing-Qiang Huang,Qiu-Yu Liu,Xian-Bin Zhang,Jun-Wei Song,Liang Wang,Chun-Hui Zhou,Peng Gong,Li-Yun Gong,Jing Zhu,He-Feng Li

doi:10.1186/s12967-021-02954-8

Abstract

BackgroundColorectal cancer is the third most common diagnosis. Oxaliplatin is used as first-line treatment of colon cancer. However, oxaliplatin resistance greatly reduces its therapeutic effect. SRPK1 involves in pre-mRNA splicing and tumorigenesis. How SRPK1 mediates drug resistance in colon cancer is unknown.MethodsThe expression of SRPK1 was analyzed in the TCGA and the CPTAC pan-cancer samples and detected in colon cancer cell lines and tissues by IHC and western blot. The MTT and TUNEL assay were used to verify the anti-apoptosis ability of colon cancer cell. The activation of NF-κB was determined by luciferase assay and qRT-PCR. AKT, IKK, IκB and their phosphorylation level were verified by western blot.ResultsWe found that SRPK1 expression was the second highest in TCGA and the CPTAC pan-cancer samples. The mRNA and protein levels of SRPK1 were increased in tissues from patients with colon cancer. SRPK1 was associated with clinical stage and TNM classifications in 148 cases of colon cancer patients. High SRPK1 levels correlated with poor prognosis (p < 0.001). SRPK1 overexpression enhanced the anti-apoptosis ability of colon cancer cells, whereas SRPK1 silencing had the opposite effect under oxaliplatin treatment. Mechanistically, SRPK1 enhances IKK kinase and IκB phosphorylation to promote NF-κB nuclear translocation to confer oxaliplatin resistance.ConclusionsOur findings suggest that SRPK1 participates in colon cancer progression and enhances the anti-apoptosis capacity to induce drug resistance in colon cancer cells via NF-κB pathway activation, and thus might be a potential pharmaceutically target for colon cancer treatment.

Highlights

Colorectal cancer is the third most common diagnosis
Our findings suggest that Serine-arginine protein kinase 1 (SRPK1) participates in colon cancer progression and enhances the antiapoptosis capacity to induce drug resistance in colon cancer cells via NF-κB pathway activation, and might be a potential pharmaceutically target for colon cancer treatment
SRPK1 is overexpressed and associated with clinical stage, TNM classification, and prognosis of survival in patients with colon cancer By analyzing the expression of SRPK1 in the Cancer Genome Atlas (TCGA) database, we found that the SRPK1 mRNA expression was the second highest in colon cancer, which was only lower than that in rectum adenocarcinoma (READ) among 33 types of cancer, and the SRPK1 mRNA expression was increased in the TCGA colon cancer tissues (n = 286) compared with that in normal tissues (n = 41) (p < 0.001) (Fig. 1a, b)

Summary

Introduction

Colorectal cancer is the third most common diagnosis. Oxaliplatin is used as first-line treatment of colon cancer. How SRPK1 mediates drug resistance in colon cancer is unknown. Huang et al J Transl Med (2021) 19:280 that participates in oxaliplatin treatment resistance in colon cancer is urgent and important. Wang et al reported that SRPK1 interferes with PH domain and leucine rich repeat protein phosphatase 1 (PHLPP1)-mediated dephosphorylation of protein kinase B (AKT). SRPK1 is related to both chemotherapy sensitivity and resistance in many cancers, including lung, prostate, male germ cell, retinoblastoma, pancreas, colon, and breast cancer [15,16,17,18,19]. The modification of SRPK1 is involved in multiple drug-resistance signaling cascades, including osmotic stress and the epidermal growth factor (EGF)-EGF receptor (EGFR)-AKT pathway [20,21,22]. SRPK1 plays an important role in tumor-associated pathway activation, which might enhance drug-resistance

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Discussion

Conclusion