Active mixture of serum-circulating small molecules selectively inhibits proliferation and triggers apoptosis in cancer cells via induction of ER stress

Dalma Scheffer, Gyula Kulcsár, György Nagyéri, Marianna Kiss-Merki, Zoltán Rékási, Magnus Maloy, Tamás Czömpöly

Research output: Contribution to journalArticle

Abstract

Genetic and epigenetic regulation as well as immune surveillance are known defense mechanisms to protect organisms from developing cancer. Based on experimental evidence, we proposed that small metabolically active molecules accumulating in cancer cells may play a role in an alternative antitumor surveillance system. Previously, we reported that treatment with a mixture of experimentally selected small molecules, usually found in the serum (defined ‘active mixture’, AM), selectively induces apoptosis in cancer cells and significantly inhibits tumor formation in vivo. In this study, we show that the AM elicits gene expression changes characteristic of endoplasmic reticulum (ER) stress in HeLa, MCF-7, PC-3 and Caco-2 cancer cells, but not in primary human renal epithelial cells. The activation of the ER stress pathway was confirmed by the upregulation of ATF3, ATF4, CHAC1, DDIT3 and GDF15 proteins. Mechanistically, our investigation revealed that eIF2α, PERK and IRE1α are phosphorylated upon treatment with the AM, linking the induction of ER stress to the antiproliferative and proapoptotic effects of the AM previously demonstrated. Inhibition of ER stress in combination with BBC3 and PMAIP1 knockdown completely abrogated the effect of the AM. Moreover, we also demonstrated that the AM induces mIR-3189-3p, which in turn enhances the expression of ATF3 and DDIT3, thus representing a possible new feedback mechanism in the regulation of ATF3 and DDIT3 during ER stress. Our results highlight small molecules as attractive anticancer agents and warrant further evaluation of the AM in cancer therapy, either alone or in combination with other ER stress inducing agents.

Original languageEnglish
Article number109426
JournalCellular Signalling
Volume65
DOIs
Publication statusPublished - Jan 2020

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Unfolded Protein Response
Endoplasmic Reticulum Stress
Apoptosis
Amino Acids
Serum
Neoplasms
Transcription Factor CHOP
Caco-2 Cells
Epigenomics
Antineoplastic Agents
Up-Regulation
Epithelial Cells
Kidney
Gene Expression

Keywords

  • Amino acids
  • Apoptosis
  • Cancer
  • ER stress
  • Unfolded protein response

ASJC Scopus subject areas

  • Cell Biology

Cite this

Active mixture of serum-circulating small molecules selectively inhibits proliferation and triggers apoptosis in cancer cells via induction of ER stress. / Scheffer, Dalma; Kulcsár, Gyula; Nagyéri, György; Kiss-Merki, Marianna; Rékási, Zoltán; Maloy, Magnus; Czömpöly, Tamás.

In: Cellular Signalling, Vol. 65, 109426, 01.2020.

Research output: Contribution to journalArticle

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