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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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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: [email protected]

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


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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