C6-ceramide induces salivary adenoid cystic carcinoma cell apoptosis via IP3R-activated UPR and UPR-independent pathways

Biochem Biophys Res Commun. 2020 May 14;525(4):997-1003. doi: 10.1016/j.bbrc.2020.02.164. Epub 2020 Mar 13.

Abstract

C6-ceramide is an exogenous short-chain ceramide which can induce apoptosis of multiple cancer cells. Salivary adenoid cystic carcinoma (SACC) is a common salivary gland cancer, which possesses of high rate of local recurrence and distant metastasis. The mechanism of ceramide-induced SACC-83 and SACC-LM cell apoptosis has not been revealed. In our study, gene expression microarray was used to discover that the unfolded protein response (UPR) pathway, especially PRKR-like endoplasmic reticulum kinase (PERK) pathway, was the major activated pathway after treatment of c6-ceramide. D1ER, an endoplasmic-reticulum-targeted Ca2+ indicator, was used to measure Ca2+ release from endoplasmic reticulum (ER) dynamically. We found that inositol 1,4,5-trisphosphate receptor 3 (IP3R3) was activated, leading to Ca2+ release from ER, soon after c6-ceramide treatment. IP3R3 silencing could block UPR, although it could not prevent SACC-83 and SACC-LM cells from apoptosis. Moreover, we found that C/EBP-homologous protein could upregulate in a UPR-independent way. Mitochondria outer membrane permeabilization might play an important role in inducing SACC cell apoptosis.

Keywords: Apoptosis; Ceramide; Inositol 1,4,5-trisphosphate receptor; Mitochondria outer membrane permeabilization; Unfolded protein response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Apoptosis / genetics
  • Calcium / metabolism
  • Carcinoma, Adenoid Cystic / genetics
  • Carcinoma, Adenoid Cystic / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Ceramides / administration & dosage
  • Ceramides / pharmacology*
  • Cytosol / drug effects
  • Cytosol / metabolism
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Silencing
  • Humans
  • Inositol 1,4,5-Trisphosphate Receptors / genetics
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism*
  • Ki-67 Antigen / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mitochondrial Membranes / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Salivary Gland Neoplasms / genetics
  • Salivary Gland Neoplasms / metabolism*
  • Signal Transduction / genetics
  • Unfolded Protein Response / drug effects*
  • Unfolded Protein Response / genetics
  • Xenograft Model Antitumor Assays
  • eIF-2 Kinase / genetics
  • eIF-2 Kinase / metabolism

Substances

  • Ceramides
  • ITPR3 protein, human
  • Inositol 1,4,5-Trisphosphate Receptors
  • Ki-67 Antigen
  • MKI67 protein, human
  • N-caproylsphingosine
  • EIF2AK3 protein, human
  • eIF-2 Kinase
  • Calcium