15d-PGJ2 as an endoplasmic reticulum stress manipulator in multiple myeloma in vitro and in vivo

Marcelo Sperandio; Ana Paula D Demasi; Elizabeth F Martinez; Sara O Saad; Fernando V Pericole; Karla P Vieira; Nadir S Freitas; Vera C Araújo; Amy Louise Brown; Juliana Trindade Clemente-Napimoga; Marcelo Henrique Napimoga

doi:10.1016/j.yexmp.2017.05.003

15d-PGJ₂ as an endoplasmic reticulum stress manipulator in multiple myeloma in vitro and in vivo

Exp Mol Pathol. 2017 Jun;102(3):434-445. doi: 10.1016/j.yexmp.2017.05.003. Epub 2017 May 12.

Affiliations

¹ Laboratory of Immunology and Molecular Biology, São Leopoldo Mandic Institute of Medicine & Dentistry and Research Center (SLMANDIC), Campinas, SP, Brazil.
² Hematology Center, State University of Campinas (UNICAMP), Campinas, SP, Brazil.
³ Laboratory of Immunology and Molecular Biology, São Leopoldo Mandic Institute of Medicine & Dentistry and Research Center (SLMANDIC), Campinas, SP, Brazil. Electronic address: [email protected].

PMID: 28506771
DOI: 10.1016/j.yexmp.2017.05.003

Abstract

Multiple myeloma (MM) is characterised by intense protein folding and, consequently endoplasmic reticulum (ER) stress. The prostaglandin 15d-PGJ₂ is able to raise oxidative stress levels within the cell and potentially trigger cell death. The aim of this study was to evaluate the antineoplastic effect of 15d-PGJ₂ on MM in vitro and in vivo via ER and oxidative stress pathways. MM.1R and MM.1S cell lines were treated with 15d-PGJ₂ at 1-10μM and evaluated with regard to proliferation, mRNA expression of PRDX1, PRDX4, GRP78, GRP94, CHOP, BCL-2 and BAX. Stress data was validated via oxidized glutathione assays. MM.1R cells were inoculated into NOD/SCID mice, which were subsequently treated daily with 15d-PGJ₂ at 4mg/kg or vehicle (control), with tumour volume being monitored for 14days. 15d-PGJ₂ reduced cell proliferation, induced cell death and apoptosis at 5μM and 10μM and Stress-related genes were upregulated at the same doses. Oxidized glutathione levels were also increased. 15d-PGJ2 at 4mg/kg in vivo halted tumour growth. In conclusion, 15d-PGJ₂ induced myeloma cell death via ER stress in vitro. 15d-PGJ2 in vivo also inhibited tumour growth.

Keywords: Antineoplastic agents; Apoptosis; Endoplasmic reticulum stress; Multiple myeloma; Peroxiredoxins; Prostaglandins; Unfolded protein response.

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Down-Regulation
Endoplasmic Reticulum Chaperone BiP
Endoplasmic Reticulum Stress / drug effects*
Heat-Shock Proteins / genetics
Heat-Shock Proteins / metabolism
Humans
Male
Membrane Glycoproteins / genetics
Membrane Glycoproteins / metabolism
Mice
Mice, Inbred NOD
Mice, SCID
Multiple Myeloma / drug therapy*
Oxidative Stress / drug effects
Peroxiredoxins / genetics
Peroxiredoxins / metabolism
Prostaglandin D2 / analogs & derivatives*
Prostaglandin D2 / pharmacology
Proto-Oncogene Proteins c-bcl-2 / genetics
Proto-Oncogene Proteins c-bcl-2 / metabolism
RNA, Messenger / genetics
RNA, Messenger / metabolism
Reproducibility of Results
Transcription Factor CHOP / genetics
Transcription Factor CHOP / metabolism
Up-Regulation
bcl-2-Associated X Protein / genetics
bcl-2-Associated X Protein / metabolism

Substances

15-deoxyprostaglandin J2
Antineoplastic Agents
BAX protein, human
BCL2 protein, human
DDIT3 protein, human
Endoplasmic Reticulum Chaperone BiP
HSPA5 protein, human
Heat-Shock Proteins
Hspa5 protein, mouse
Membrane Glycoproteins
Proto-Oncogene Proteins c-bcl-2
RNA, Messenger
bcl-2-Associated X Protein
endoplasmin
Transcription Factor CHOP
PRDX1 protein, human
PRDX4 protein, human
Peroxiredoxins
Prostaglandin D2