Knockdown of Stromal Interaction Molecule 1 (STIM1) Suppresses Acute Myeloid Leukemia Cell Line Survival Through Inhibition of Reactive Oxygen Species Activities

Author(s):  
Eman Salem Algariri ◽  
Rabiatul Basria S. M. N. Mydin ◽  
Emmanuel Jairaj Moses ◽  
Simon Imakwu Okekpa ◽  
Nur Arzuar Abdul Rahim ◽  
...  

Abstract Stromal interaction molecule 1 (STIM1) is a critical regulator of calcium homeostasis through store-operated calcium entry (SOCE) and recently considered a potential therapeutic target for cancer. However, the role of STIM1 in acute myeloid leukemia (AML) remains unclear. The present study investigates the role of STIM1 in AML cell line (THP-1) proliferation and survival and its effect on reactive oxygen species (ROS) activities. Dicer-substrate siRNA (dsiRNA) - mediated STIM1 knockdown inhibited the THP-1 cells proliferation and colony formation ability. Further observation on ROS profile showed a significant reduction in the ROS level, which was associated with a significant down-regulation of NOX2 and protein kinase C (PKC). Furthermore, STIM1 knockdown exhibited significant down-regulation of Akt, KRAS, and MAPK which are critical proliferative and survival pathway-related genes. This study unveiled the importance of STIM1 in the regulation of AML cells proliferation and survival which could be through maintaining ROS at level keeping the proliferative and survival pathways at an active state. These findings represent STIM1 as a potential therapeutic target for AML treatment.

Blood ◽  
2021 ◽  
Author(s):  
Huan Cai ◽  
Makoto Kondo ◽  
Lakshmi Sandhow ◽  
Pingnan Xiao ◽  
Anne-Sofie Johansson ◽  
...  

Impairement of normal hmatopoiesis and leukemia progression are two well-linked processes during leukemia development and controlled by the bone marrow (BM) niche. Extracellular matrix proteins including laminin are important BM niche components. However, their role in hematopoiesis regeneration and leukemia is unknown. Laminin α4 (Lama4), a major receptor-binding chain of several laminins, is altered in BM niches in mice with acute myeloid leukemia (AML). So far, the impact of Lama4 on leukemia progression remains unknown. We here report that Lama4 deletion in mice resulted in impaired hematopoiesis regeneration following irradiation-induced stress, which is accompanied with altered BM niche composition and inflammation. Importantly, in a transplantation-induced MLL-AF9 AML mouse model, we demonstrate accelerated AML progression and relapse in Lama4-/-mice. Upon AML exposure, Lama4-/- mesenchymal stem cells (MSCs) exhibited dramatic molecular alterations including upregulation of inflammatory cytokines that favor AML growth. Lama4-/- MSCs displayed increased anti-oxidant activities and promoted AML stem cell proliferation and chemoresistance to cytarabine, which was accompanied by increased mitochondrial transfer from the MSCs to AML cells and reduced reactive oxygen species in AML cells in vitro. Similarly, we detected lower levels of reactive oxygen species in AML cells from Lama4-/- mice post-cytarabine treatment. Notably, LAMA4 inhibition or knockdown in human MSCs promoted human AML cell proliferation and chemoprotection. Together, our study for the first time demonstrates a critical role of Lama4 in impeding AML progression and chemoresistance. Targeting Lama4 signaling pathways may offer potential new therapeutic options for AML.


2019 ◽  
Vol 9 ◽  
Author(s):  
Laura Monaghan ◽  
Matthew E. Massett ◽  
Roderick P. Bunschoten ◽  
Alex Hoose ◽  
Petrisor-Alin Pirvan ◽  
...  

2020 ◽  
Vol 26 (1) ◽  
Author(s):  
Chong Wang ◽  
Lingling Li ◽  
Mengya Li ◽  
Weiqiong Wang ◽  
Yanfang Liu ◽  
...  

Abstract Background Long non-coding RNAs (lncRNAs) are biomarkers participating in multiple disease development including acute myeloid leukemia (AML). Here, we investigated molecular mechanism of X Inactive-Specific Transcript (XIST) in regulating cellular viability, apoptosis and drug resistance in AML. Methods XIST, miR-29a and myelocytomatosis oncogene (MYC) expression in AML bone marrow cells collected from 62 patients was evaluated by RT-qPCR and Western blot analysis. Besides, the relationship among XIST, miR-29a and MYC was analyzed by dual luciferase reporter assay, RIP, and RNA pull down assays. AML KG-1 cells were treated with anti-tumor drug Adriamycin. The role of XIST/miR-29a/MYC in cellular viability, apoptosis and drug resistance in AML was accessed via gain- and loss-of-function approaches. At last, we evaluated role of XIST/miR-29a/MYC on tumorigenesis in vivo. Results XIST and MYC were up-regulated, and miR-29a was down-regulated in AML bone marrow cells. Silencing XIST inhibited cellular activity and drug resistance but promoted cellular apoptosis of KG-1 cells by down-regulating MYC. XIST inhibited miR-29a expression to up-regulate MYC. Moreover, silencing XIST inhibited tumorigenesis of AML cells in vivo. Conclusions Overall, down-regulation of XIST decreased MYC expression through releasing the inhibition on miR-29a, thereby reducing drug resistance, inhibiting viability and promoting apoptosis of AML cells.


2019 ◽  
Vol 17 (6) ◽  
pp. 1241-1252 ◽  
Author(s):  
Lisa E. Richter ◽  
Yiqian Wang ◽  
Michelle E. Becker ◽  
Rachel A. Coburn ◽  
Jacob T. Williams ◽  
...  

2013 ◽  
Vol 86 (10) ◽  
pp. 1430-1440 ◽  
Author(s):  
Li-Yuan Bai ◽  
Jing-Ru Weng ◽  
Chang-Fang Chiu ◽  
Chia-Yung Wu ◽  
Su-Peng Yeh ◽  
...  

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