Silencing of LRRFIP1 enhances the sensitivity of gemcitabine in pancreatic cancer cells by activating JNK/c-Jun signaling

Pancreatology. 2021 Jun;21(4):771-778. doi: 10.1016/j.pan.2021.02.018. Epub 2021 Mar 3.

Abstract

Background: The epithelial-mesenchymal transition (EMT) in cancer cells has been shown to closely associate with the survival and drug resistance of cancer cells. We recently provided evidence that Wnt signal activator leucine-rich repeat in flightless-1-interacting protein 1 (LRRFIP1) regulates EMT in pancreatic cancer. LRRFIP1 silencing inhibits the translocation of β-catenin to the nucleus, which led to reverse EMT in cancer cells. It was suggested that LRRFIP1 was implicated in gemcitabine sensitivity by regulating EMT signaling.

Methods: Gemcitabine chemosensitivity was investigated in LRRFIP1-knockdown pancreatic cancer cells (PANC-1 and MIA Paca-2). In addition, the effects of LRRFIP1 knockdown on JNK/SAPK (stress activated-protein kinase) signaling and apoptosis were evaluated.

Results: LRRFIP1 silencing accelerates gemcitabine-induced caspase activity and cell death in pancreatic cancer cells. It was also revealed that gemcitabine-induced phosphorylation of c-Jun N-terminal kinase (JNK) and c-Jun were increased in LRRFIP1 knockdown cells. The activation of JNK/c-Jun in LRRFIP1-knockdown cells was significantly diminished by the inhibition of Rac activity. It was confirmed that the acquisition of gemcitabine sensitivity by LRRFIP1 silencing largely depends on the stimulation of JNK/SAPK (stress activated-protein kinase) signaling.

Conclusions: Our findings suggest that reversing EMT and transient activation of JNK might be essential for the gemcitabine sensitivity in LRRFIP1 knockdown pancreatic cancer cells. Our discoveries highlight the potential role of LRRFIP1 in the chemosensitivity related to the regulation of EMT signaling.

Keywords: Gemcitabine; JNK; JNK/SAPK signal; LRRFIP1; Wnt signal; c-Jun.

MeSH terms

  • Cell Line, Tumor
  • Deoxycytidine* / analogs & derivatives
  • Deoxycytidine* / pharmacology
  • Humans
  • JNK Mitogen-Activated Protein Kinases / genetics
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Pancreatic Neoplasms* / drug therapy
  • Pancreatic Neoplasms* / genetics
  • RNA-Binding Proteins

Substances

  • LRRFIP1 protein, human
  • RNA-Binding Proteins
  • Deoxycytidine
  • gemcitabine
  • JNK Mitogen-Activated Protein Kinases

Supplementary concepts

  • Pancreatic Carcinoma