scholarly journals Deptor transcriptionally regulates endoplasmic reticulum homeostasis in multiple myeloma cells

Oncotarget ◽  
2016 ◽  
Vol 7 (43) ◽  
pp. 70546-70558 ◽  
Author(s):  
Valeria Catena ◽  
Tiziana Bruno ◽  
Francesca De Nicola ◽  
Frauke Goeman ◽  
Matteo Pallocca ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Endoplasmic Reticulum ◽  
Myeloma Cells

scholarly journals Novel p97/ VCP inhibitor induces endoplasmic reticulum stress and apoptosis in both bortezomib‐sensitive and ‐resistant multiple myeloma cells

2019 ◽  
Vol 110 (10) ◽  
pp. 3275-3287 ◽  
Author(s):  
Nao Nishimura ◽  
Mohamed O. Radwan ◽  
Masayuki Amano ◽  
Shinya Endo ◽  
Eri Fujii ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Myeloma Cells

scholarly journals High endoplasmic reticulum activity renders multiple myeloma cells hypersensitive to mitochondrial inhibitors

2009 ◽  
Vol 66 (1) ◽  
pp. 129-140 ◽  
Author(s):  
Metin Kurtoglu ◽  
Katherine Philips ◽  
Huaping Liu ◽  
Lawrence H. Boise ◽  
Theodore J. Lampidis
Keyword(s):  
Multiple Myeloma ◽  
Endoplasmic Reticulum ◽  
Myeloma Cells ◽  
Mitochondrial Inhibitors

A Small Molecule, Shikonin, Dually Functions As a Proteasome Inhibitor and a Necroptosis Inducer In Multiple Myeloma Cells

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3172-3172 ◽  
Author(s):  
Naoko Wada ◽  
Yawara Kawano ◽  
Shiho Fujiwara ◽  
Yoshitaka Kikukawa ◽  
Yutaka Okuno ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Cell Line ◽  
Small Molecule ◽  
Proteasome Inhibitor ◽  
Myeloma Cells ◽  
Ubiquitinated Proteins ◽  
Low Concentrations

Abstract Background Despite of recent advances in therapeutic strategy for multiple myeloma (MM), MM still remains incurable and novel therapeutic approach is urgently needed. We have previously demonstrated that a natural small molecule, shikonin (SHK), induced both apoptosis and necroptosis (programmed necrosis) in MM cells. In this study, we attempted to elucidate biological mechanisms of SHK in inducing apoptosis and necroptosis. Methods Six MM cell lines, KMS-12-PE, RPMI 8226, U266, KMM1, KMS-11 and a bortezomib-resistant MM cell line, KMS-11/BTZ (obtained from Kyowa Hakko Kirin Co. Ltd.), were utilized. Inhibitors of pan-caspase and necroptosis, ZVAD-fmk and Nec-1 (necrostatin-1), were employed to distinguish apoptosis and necroptosis, respectively. Cell death was analyzed using the trypan blue dye exclusion method (WST-8 assay) and flow cytometry analysis using AnnexinV/PI staining. Morphological examinations of cells were performed with May Giemza staining. Caspases, RIP1, ubiquitinated proteins, and heat shock proteins were analyzed with western blot. Knockdown of RIP1, an essential molecule for necroptosis, was performed using siRNA. ER stress was assessed by detecting activated XBP-1, which was analyzed by digestion of PCR products with ApaLI. Because the ApaLI site in XBP-1 mRNA is spliced out upon activation, the activated XBP-1 shows one large band after ApaLI digestion, while inactivated XBP-1 shows two ApaI-digested bands. Thapsigargin, sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) inhibitor, was used as an ER stress inducer. Results By screening natural compounds libraries (provided by Institute of Natural Medicine, Toyama University, Japan), we found that SHK, a natural compound derived from the root of Lithospermum erythrorhizon, induced cell death in MM cells. Apoptosis was induced at a relatively low concentration (2.5∼5 µM) and was inhibited by a caspase-inhibitor, while necroptosis was promptly induced at higher concentrations (10∼ 20 µM) within 5 hours and was completely inhibited by Nec-1. Morphological analysis showed that SHK at low concentrations induced typical apoptotic changes, such as fragmented nucleus, while SHK at higher concentrations induced necrotic morphology, such as translucent cytoplasm and swelling of cell membranes. By contrast, SHK did not induce apoptosis or necrptosis in peripheral blood mononuclear cells from healthy donors at low concentrations. SHK activated caspase-8 and -3 at low concentrations but did not at higher concentrations. RIP1, an essential molecule for necroptosis, was cleaved after treatment with SHK at low concentrations, which leads to the inhibition of necroptosis, while it was not cleaved and remained active at higher concentrations, suggesting that SHK dynamically regulates the cleavage of RIP-1. At low concentrations, shikonin induced an accumulation of ubiquitinated proteins and activated XBP-1, suggesting SHK may have a property of proteasome inhibitor eventually inducing endoplasmic reticulum stress. Finally, SHK at low concentration killed bortezomib resistant cells with lower IC50 comparing to that of the parental cells (0.91 vs 1.56 µM, respectively). Conclusions We here report, for the first time, that SHK induces apoptosis and necroptosis in MM cells at low and high concentrations, respectively, by regulating proteasome function and RIP-1 cleavage. Given the fact that SHK efficiently induces cell death in bortezomib-resistant cell line, SHK may act as a novel proteasome inhibitor for bortezomib-resistant myeloma cells. Moreover, SHK at higher concentrations, which induces nectoptosis, should be an attractive future therapeutic option potentially to eradicate MM cells. Disclosures: No relevant conflicts of interest to declare.

Betulinic Acid Enhances the Sensitivity of Multiple Myeloma Cells to Bortezomib by the Inactivation of the AKT/mTOR Pathway

2020 ◽  
Vol 18 (3) ◽  
pp. 241-246
Author(s):  
Yu Dan ◽  
Wan Sheng ◽  
Hu Lili
Keyword(s):  
Multiple Myeloma ◽  
Betulinic Acid ◽  
Myeloma Cell ◽  
Mtor Pathway ◽  
Prolonged Treatment ◽  
Myeloma Cells ◽  
Multiple Myeloma Cell ◽  
Increased Sensitivity ◽  
Colony Number ◽  
Rpmi 8226

This study aimed to investigate the mechanism of betulinic acid on multiple myeloma cell resistance to bortezomib. To this end, the bortezomib-resistant RPMI-8226-R cells were generated by prolonged treatment of RPMI-8226 cells with increasing concentrations of bortezomib. Based on the measurements of cell viability and colony number, RPMI-8226-R cells exhibited enhanced resistance to bortezomib than RPMI-8226 cells. Treatment with betulinic acid resulted in increased sensitivity of RPMI-8226-R to bortezomib. When RPMI-8226-R cells were co-treated with bortezomib and betulinic acid, there was an increase in apoptosis rate, cleaved caspase-3, cleaved caspase-9 expression and the decrease in p-AKT/AKT and p-mTOR/mTOR levels. These results suggest that betulinic acid enhances the sensitivity of RPMI-8226-R cells to bortezomib by inhibiting the activation of the AKT/mTOR pathway in bortezomib-resistant multiple myeloma cells.

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