Pan-sigma receptor modulator rc-106 induces terminal unfolded protein response in in vitro pancreatic cancer model

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Abstract

Pancreatic cancer (PC) remains one of the most lethal cancers worldwide. Sigma receptors (SRs) have been proposed as cancer therapeutic targets. Their main localization suggests they play a potential role in ER stress and in the triggering of the unfolded protein response (UPR). Here, we investigated the mechanisms of action of RC-106, a novel pan-SR modulator, to characterize therapeutically exploitable role of SRs in tumors. Two PC cell lines were used in all the experiments. Terminal UPR activation was evaluated by quantifying BiP, ATF4 and CHOP by Real-Time qRT-PCR, Western Blot, immunofluorescence and confocal microscopy. Cell death was studied by flow cytometry. Post-transcriptional gene silencing was performed to study the interactions between SRs and UPR key proteins. RC-106 activated ER stress sensors in a dose-and time-dependent manner. It also induced ROS production accordingly with ATF4 upregulation at the same time reducing cell viability of both cell lines tested. Moreover, RC-106 exerted its effect through the induction of the terminal UPR, as shown by the activation of some of the main transducers of this pathway. Post-transcriptional silencing studies confirmed the connection between SRs and these key proteins. Overall, our data highlighted a key role of SRs in the activation of the terminal UPR pathway, thus indicating pan-SR ligands as candidates for targeting the UPR in pancreatic cancer.

Original languageEnglish
Article number9012
Pages (from-to)1-19
Number of pages19
JournalInternational Journal of Molecular Sciences
Volume21
Issue number23
DOIs
Publication statusPublished - Dec 1 2020

Keywords

  • ER stress
  • Gatekeepers
  • Pancreatic cancer
  • ROS
  • Sigma receptors
  • UPR

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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