Oncotarget

Research Papers:

Endoplasmic reticulum stress induces autophagy and apoptosis while inhibiting proliferation and drug resistance in multiple myeloma through the PI3K/Akt/mTOR signaling pathway

Yun-Feng Fu, Xiao Liu, Meng Gao, Ya-Nan Zhang and Jing Liu _

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Oncotarget. 2017; 8:61093-61106. https://doi.org/10.18632/oncotarget.17862

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Abstract

Yun-Feng Fu1,*, Xiao Liu1,*, Meng Gao1, Ya-Nan Zhang1 and Jing Liu1

1The Third Xiangya Hospital of Central South University, Changsha 410013, P.R. China

*These authors have contributed equally to this work

Correspondence to:

Jing Liu, email: jjliuliuyswq@126.com

Keywords: multiple myeloma, endoplasmic reticulum stress, PI3K/Akt/mTOR signaling pathway, autophagy, apoptosis

Received: December 30, 2016     Accepted: April 18, 2017     Published: May 15, 2017

ABSTRACT

We investigated the effects of endoplasmic reticulum stress (ERS) on autophagy, proliferation, apoptosis, and drug resistance in multiple myeloma (MM). MM patients enrolled in our study (n = 268) were classified into sensitive and resistant groups based on chemotherapy efficacy, and their serum levels of β2-MG, albumin (ALB), lactic dehydrogenase (LDH), Ca2+ and hemoglobin were determined. In addition, human MM U266 and MOLP-2/R cells were divided into blank, tunicamycin (TM), TM + insulin-like growth factor-1 (IGF-1), and TM + rapamycin groups, and measured expression of ERS-related, PI3K/Akt/mTOR pathway-related, and autophagy-related mRNA and proteins. Serum levels of β2-MG, LDH and Ca2+, and expression of PI3K, Akt, and mTOR were higher in the resistant than sensitive group. Serum levels of ALB and hemoglobin, and expression of glucose-regulated protein 78 (GRP78), GRP94, microtubule associated protein 1 light chain 3 (LC3), and Beclin1, were lower in the resistant than sensitive group. In U266 cells treated with TM and IGF-1 or rapamycin, ERS promoted autophagy and apoptosis while inhibiting proliferation through inhibition of PI3K/Akt/mTOR signaling. ERS also reversed drug resistance in MOLP-2/R cells via the PI3K/Akt/mTOR signaling pathway. These data suggest that ERS activation could be exploited for therapeutic benefits in the treatment of MM.


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