Serine/arginine protein-specific kinase 2 promotes the development and progression of pancreatic cancer by downregulating Numb and p53

FEBS J. 2019 May;286(9):1668-1682. doi: 10.1111/febs.14778. Epub 2019 Mar 1.

Abstract

Serine/arginine protein-specific kinase 2 (SRPK2) plays a vital role in the progression of a range of different malignancies, including pancreatic cancer. However, the mechanisms are poorly understood. Previous studies have shown that in hepatocellular carcinoma, SRPK2 knockdown leads to the upregulation of the cell fate determining protein Numb, and in pancreatic cancer cells, Numb knockdown prevents ubiquitin-mediated degradation of p53. In this study, we investigated the relationship between SRPK2, Numb and p53 in the development of pancreatic cancer with or without chemical agent treatment in vitro. SRPK2 expression was upregulated in pancreatic cancer tissues and associated with decreased overall survival in pancreatic cancer patients, indicating that expression of this protein can be used as a marker of unfavourable prognosis. Expression of SRPK2 was positively associated with tumour T stage and Union for International Cancer Control (UICC) stage, and negatively associated with Numb expression in serial tissue sections. In pancreatic cancer cells, SRPK2 downregulation or overexpression led to modulation of Numb and wild-type p53 protein expression in response to oxaliplatin treatment. Furthermore, these three endogenous proteins could be coimmunoprecipitated as a triple complex. Numb or p53 knockdown reversed the upregulation of p53 that was induced by silencing SRPK2. SRPK2 overexpression promoted cell invasion and migration, and decreased chemosensitivity of cancer cells to gemcitabine or oxaliplatin treatment. Conversely, SRPK2 silencing decreased cell invasion and migration and increased chemosensitivity; these effects were reversed by silencing p53 in oxaliplatin-treated pancreatic cancer cells. Our data suggest that SRPK2 negatively regulates p53 by downregulating Numb under chemical agent treatment. Thus, SRPK2 promotes the development and progression of pancreatic cancer in a p53-dependent manner.

Keywords: Numb; SRPK2; p53; pancreatic cancer; progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antineoplastic Agents / pharmacology
  • Biomarkers, Tumor
  • Cell Line, Tumor
  • Cell Movement
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Disease Progression
  • Drug Resistance, Neoplasm
  • Female
  • Gemcitabine
  • Gene Expression Regulation, Neoplastic* / drug effects
  • Gene Silencing
  • Humans
  • Kaplan-Meier Estimate
  • Liver Neoplasms / secondary
  • Male
  • Membrane Proteins / biosynthesis*
  • Membrane Proteins / genetics
  • Middle Aged
  • Neoplasm Invasiveness
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Neoplasm Staging
  • Nerve Tissue Proteins / biosynthesis*
  • Nerve Tissue Proteins / genetics
  • Oxaliplatin / pharmacology
  • Pancreatic Neoplasms / enzymology*
  • Pancreatic Neoplasms / mortality
  • Pancreatic Neoplasms / pathology
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / biosynthesis
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / physiology*
  • Tumor Suppressor Protein p53 / antagonists & inhibitors
  • Tumor Suppressor Protein p53 / biosynthesis*
  • Tumor Suppressor Protein p53 / genetics

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Membrane Proteins
  • Neoplasm Proteins
  • Nerve Tissue Proteins
  • Numb protein, human
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Oxaliplatin
  • Deoxycytidine
  • Protein Serine-Threonine Kinases
  • SRPK2 protein, human
  • Gemcitabine