Bcr-Abl reduces endoplasmic reticulum releasable calcium levels by a Bcl-2–independent mechanism and inhibits calcium-dependent apoptotic signaling

Blood ◽  
2006 ◽  
Vol 107 (10) ◽  
pp. 4003-4010 ◽  
Author(s):  
Katarzyna Piwocka ◽  
Susanne Vejda ◽  
Thomas G. Cotter ◽  
Gerald C. O'Sullivan ◽  
Sharon L. McKenna
Keyword(s):  
Drug Resistance ◽  
Endoplasmic Reticulum ◽  
Disease Progression ◽  
Molecular Mechanisms ◽  
Blast Crisis ◽  
Apoptotic Signaling ◽  
Calcium Dependent ◽  
Established Cell ◽  
Apoptotic Pathways ◽  
Mitochondrial Calcium Uptake

The Bcr-Abl oncoprotein plays a major role in the development and progression of chronic myeloid leukemia (CML). Several studies have suggested that the expression levels of Bcr-Abl are elevated at disease progression to blast crisis and that this plays a significant role in the achievement of drug resistance. We have established cell lines expressing low and high levels of Bcr-Abl to study the molecular mechanisms involved in disease progression and drug resistance. It is now known that the endoplasmic reticulum (ER) can play a major role in the regulation of apoptosis. We therefore investigated whether Bcr-Abl expression modulates ER homeostasis and interferes with ER-mediated apoptotic pathways to promote survival. Bcr-Abl–expressing cells exhibit a decreased amount of free releasable calcium in the ER as well as a weaker capacitative calcium entry response, relative to parental cells. This effect is independent of Bcl-2, which is a known modulator of ER calcium homeostasis. The reduction in ER releasable calcium results in inhibition of the ER/mitochondria-coupling process and mitochondrial calcium uptake. This study demonstrates a novel downstream consequence of Bcr-Abl signaling. The ability to negate calcium-dependent apoptotic signaling is likely to be a major prosurvival mechanism in Bcr-Abl–expressing cells.

A Novel Bcr-Abl Mediated Pro-Survival Pathway: Reduction of Releasable Calcium Levels in the Endoplasmic Reticulum Inhibits Calcium Dependent Apoptotic Signaling.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2621-2621
Author(s):  
Susanne Vejda ◽  
Katarzyna Piwocka ◽  
Thomas G. Cotter ◽  
Gerald C. O’Sullivan ◽  
Sharon L. McKenna
Keyword(s):  
Drug Resistance ◽  
Endoplasmic Reticulum ◽  
Disease Progression ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Transformed Cells ◽  
Apoptotic Signaling ◽  
Calcium Dependent ◽  
Transformed Cell Lines ◽  
Er Calcium

Abstract The Bcr-Abl oncoprotein plays a major role in the development and progression of chronic myeloid leukemia (CML). Several studies have suggested that the expression levels of Bcr-Abl are elevated at disease progression to blast crisis (BC) and that this plays significant role in the achievement of drug resistance. We have established cell lines expressing low (C2 cells) and high levels (C4 cells) of Bcr-Abl to study the molecular mechanisms involved in disease progression especially with regard to drug resistance. Microarray analysis revealed that Bcr-Abl expressing cells exhibit increased expression of various endoplasmic reticulum (ER) resident proteins indicating that the ER is a novel target of Bcr-Abl. Recently, this organelle has been described as an important apoptotic gateway. Indeed, by measuring calcium levels (steady state and following drug treatment) in the ER and cytoplasm we could elucidate that the calcium dependent apoptotic signaling is disturbed in Bcr-Abl transformed cells. Moreover, inhibition of Bcr-Abl activity by Imatinib reversed this phenotype indicating that Bcr-Abl is directly modulating calcium homeostasis by yet unknown mechanisms. Two Bcr-Abl expressing human cell lines, K562 and BV173, also showed reduced amounts of calcium in the ER compared to the Bcr-Abl negative cell lines HL60 and Jurkat. Etoposide was chosen for apoptosis induction as this drug was classified to target not only the mitochondria (classical mitochondrial pathway) but also the ER (calcium dependent apoptotic pathway). Cell death was induced in the parental and Bcr-Abl transformed cell lines and calcium changes in the cytosol and the mitochondria were measured using organelle specific calcium probes. In C2 and C4 cells an early mitochondrial calcium overload was absent possibly due to the decreased amount of free releasable calcium in the ER. Moreover, other ER/calcium activated pathways were greatly diminished, such as cytosolic calcium elevation and calpain activation during apoptosis. It has been shown that decreased levels of releasable calcium in the ER is associated with cell survival. It is possible therefore that Bcr-Abl may exert some of its pro-survival or anti-apoptotic effects at the ER, by directly influencing the levels of releasable calcium. This study demonstrates a novel downstream consequence of Bcr-Abl signaling. The ability to negate calcium dependent apoptotic signaling is likely to be a major pro-survival mechanism in Bcr-Abl transformed cells.

scholarly journals Inhibition of apoptosis may lead to the development of bortezomib resistance in multiple myeloma cancer cells

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Emine Öksüzoğlu ◽  
Gül Kozalak
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Plasma Cells ◽  
Expression Levels ◽  
Diphenyltetrazolium Bromide ◽  
Apoptotic Pathways ◽  
Resistant Cells

AbstractBackgroundMultiple myeloma (MM), a malignancy of plasma cells, is the second most prevalent hematological cancer. Bortezomib is the most effective chemotherapeutic drug used in treatment. However, drug-resistance prevents success of chemotherapy. One of the factors causing drug-resistance is dysfunction of apoptotic-pathways. This study aimed to evaluate the relationship between expression levels of Bcl-2, Bax, caspase-3 and p-53 genes involved in apoptosis and the development of bortezomib-resistance in MM cell lines.Materials and methodsMultiple myeloma KMS20 (bortezomib-resistant) and KMS28 (bortezomib-sensitive) cell lines were used. 3-[4,5-Dimethylthiazol-2-yl] 1-2,5-diphenyltetrazolium bromide (MTT) assay was performed to determine IC50 values of bortezomib. RNAs were isolated from bortezomib-treated cell lines, followed by cDNA synthesis. Expression levels of the genes were analyzed by using q-Realtime-PCR.ResultsAs a result, Bcl-2/Bax ratio was higher in KMS20 (resistant) cells than in KMS28 (sensitive) cells. Expression of caspase-3 decreased in KMS20-cells, whereas increased in KMS28-cells. The results indicate that apoptosis was suppressed in resistant cells.ConclusionThese findings will enable us to understand the molecular mechanisms leading to drug-resistance in MM cells and to develop new methods to prevent the resistance. Consequently, preventing the development of bortezomib resistance by eliminating the factors which suppress apoptosis may be a new hope for MM treatment.

scholarly journals Mechanisms Underlying Taurine Protection Against Glutamate-Induced Neurotoxicity

2013 ◽  
Vol 40 (5) ◽  
pp. 628-634 ◽  
Author(s):  
Hai-Bo Ye ◽  
Hai-Bo Shi ◽  
Shan-Kai Yin
Keyword(s):  
Endoplasmic Reticulum ◽  
Plasma Membrane ◽  
Molecular Mechanisms ◽  
Membrane Depolarization ◽  
Enzymatic Activities ◽  
Intracellular Free Calcium ◽  
Free Calcium ◽  
Protective Processes ◽  
Apoptotic Pathways ◽  
Energy Failure

Abstract:Taurine appears to exert potent protections against glutamate (Glu)-induced injury to neurons, but the underlying molecular mechanisms are not fully understood. The possibly protected targets consist of the plasma membrane and the mitochondrial as well as endoplasmic reticulum (ER) membranes. Protection may be provided through a variety of effects, including the prevention of membrane depolarization, neuronal excitotoxicity and mitochondrial energy failure, increases in intracellular free calcium ([Ca2+]i), activation of calpain, and reduction of Bcl-2 levels. These activities are likely to be linked spatially and temporally in the neuroprotective functions of taurine. In addition, events that occur downstream of Glu stimulation, including altered enzymatic activities, apoptotic pathways, and necrosis triggered by the increased [Ca2+]i, can be inhibited by taurine. This review discusses the possible molecular mechanisms of taurine against Glu-induced neuronal injury, providing a better understanding of the protective processes, which might be helpful in the development of novel interventional strategies.

scholarly journals Molecular Mechanisms Associated with ROR1-Mediated Drug Resistance: Crosstalk with Hippo-YAP/TAZ and BMI-1 Pathways

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 812 ◽  
Author(s):  
Hanna Karvonen ◽  
Harlan Barker ◽  
Laura Kaleva ◽  
Wilhelmiina Niininen ◽  
Daniela Ungureanu
Keyword(s):  
Drug Resistance ◽  
Disease Progression ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Treatment Resistance ◽  
Orphan Receptor ◽  
Oncogenic Signaling ◽  
Aberrant Expression ◽  
Mesenchymal Transition ◽  
Signaling Activation

Signaling via the Wnt-related receptor tyrosine kinase-like orphan receptor 1 (ROR1) triggers tumorigenic features associated with cancer stem cells (CSCs) and epithelial–mesenchymal transition (EMT), while aberrant expression of ROR1 is strongly linked to advanced disease progression and chemoresistance. Several recent studies have shown that Wnt5a binding to ROR1 promotes oncogenic signaling by activating multiple pathways such as RhoA/Rac1 GTPases and PI3K/AKT, which in turn could induce transcriptional coactivator YAP/TAZ or polycomb complex protein BMI-1 signaling, respectively, to sustain stemness, metastasis and ultimately drug-resistance. These data point towards a new feedback loop during cancer development, linking Wnt5a-ROR1 signaling activation to YAP/TAZ or BMI-1 upregulation that could play an important role in disease progression and treatment resistance. This review focuses on the crosstalk between Wnt5a-ROR1 and YAP/TAZ or the BMI-1 signaling network, together with the current advancements in targeted strategies for ROR1-positive cancers.

The Y-box binding protein YB-1 is associated with progressive disease and mediates survival and drug resistance in multiple myeloma

Blood ◽  
2008 ◽  
Vol 111 (7) ◽  
pp. 3714-3722 ◽  
Author(s):  
Manik Chatterjee ◽  
Christoph Rancso ◽  
Thorsten Stühmer ◽  
Niels Eckstein ◽  
Mindaugas Andrulis ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Disease Progression ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Binding Protein ◽  
Ki 67 ◽  
Induced Apoptosis

Abstract Current knowledge about molecular mechanisms underlying disease progression and drug resistance in multiple myeloma (MM) is still limited. Here, we analyzed the potential pathogenetic role of the Y-box binding protein YB-1 in MM. YB-1 is a member of the cold-shock domain protein superfamily and involved in various cellular functions such as proliferation. Immunohistochemical analyses revealed that neither normal bone marrow (BM) plasma cells (PCs), premalignant PCs of patients with monoclonal gammopathy of unknown significance (MGUS), nor MM cells with a mature morphology showed expression of YB-1 in situ. In contrast, YB-1 was strongly expressed in situ in normal PC precursor blasts as well as in a MM subset and in vitro in all of the evaluated MM cell lines. The YB-1–expressing MM cells were characterized by an immature morphology and a highly proliferative phenotype as defined by Ki 67 expression. We observed that siRNA-mediated knockdown of YB-1 decreased proliferation and induced apoptosis in MM cells even in the presence of BM stromal cells. Furthermore, we found that overexpression of YB-1 mediated resistance toward doxorubicin-induced apoptosis in MM cells. Thus, YB-1 contributes to disease progression, survival, and drug resistance in MM and might therefore provide an attractive therapeutic target.

E6 and E7 oncoproteins: Potential targets of cervical cancer

2020 ◽  
Vol 27 ◽  
Author(s):  
Ramarao Malla ◽  
Mohammad Amjad Kamal
Keyword(s):  
Cervical Cancer ◽  
Drug Resistance ◽  
Host Cell ◽  
Molecular Mechanisms ◽  
Immune Therapy ◽  
Cervical Lesions ◽  
Diagnostic Strategies ◽  
E6 And E7 Oncoproteins ◽  
E6 And E7

: Cervical cancer (CC) is the fourth leading cancer in women in the age group 15-44 globally. Experimental as well as epidemiological studies identified that type16 and 18 HPV cause 70% of precancerous cervical lesions as well as cervical cancer worldwide by bringing about genetic as well as epigenetic changes in the host genome. The insertion of the HPV genome triggers various defense mechanisms including the silencing of tumor suppressor genes as well as activation of oncogenes associated with cancer metastatic pathway. E6 and E7 are small oncoproteins consisting of 150 and 100 amino acids respectively. These oncoproteins affect the regulation of the host cell cycle by interfering with p53 and pRb. Further these oncoproteins adversely affect the normal functions of the host cell by binding to their signaling proteins. Recent studies demonstrated that E6 and E7 oncoproteins are potential targets for CC. Therefore, this review discusses the role of E6 and E7 oncoproteins in metastasis and drug resistance as well as their regulation, early oncogene mediated signaling pathways. This review also uncovers the recent updates on molecular mechanisms of E6 and E7 mediated phytotherapy, gene therapy, immune therapy, and vaccine strategies as well as diagnosis through precision testing. Therefore, understanding the potential role of E6/E7 in metastasis and drug resistance along with targeted treatment, vaccine, and precision diagnostic strategies could be useful for the prevention and treatment of cervical cancer.

scholarly journals Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1715
Author(s):  
Macus Hao-Ran Bao ◽  
Carmen Chak-Lui Wong
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Liver Cancer ◽  
Effective Treatment ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Metabolic Reprogramming ◽  
Combination Therapies ◽  
Low Oxygen ◽  
Treatment Regimens

Hypoxia, low oxygen (O2) level, is a hallmark of solid cancers, especially hepatocellular carcinoma (HCC), one of the most common and fatal cancers worldwide. Hypoxia contributes to drug resistance in cancer through various molecular mechanisms. In this review, we particularly focus on the roles of hypoxia-inducible factor (HIF)-mediated metabolic reprogramming in drug resistance in HCC. Combination therapies targeting hypoxia-induced metabolic enzymes to overcome drug resistance will also be summarized. Acquisition of drug resistance is the major cause of unsatisfactory clinical outcomes of existing HCC treatments. Extra efforts to identify novel mechanisms to combat refractory hypoxic HCC are warranted for the development of more effective treatment regimens for HCC patients.

scholarly journals Genetic mapping and transcriptomic characterization of a new fuzzless-tufted cottonseed mutant

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Qian-Hao Zhu ◽  
Warwick Stiller ◽  
Philippe Moncuquet ◽  
Stuart Gordon ◽  
Yuman Yuan ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Agronomic Traits ◽  
Gene Families ◽  
Mutant Phenotype ◽  
Wild Type ◽  
Calcium Dependent ◽  
Dependent Protein ◽  
Flanking Region ◽  
Comparative Transcriptomic Analysis

Abstract Fiber mutants are unique and valuable resources for understanding the genetic and molecular mechanisms controlling initiation and development of cotton fibers that are extremely elongated single epidermal cells protruding from the seed coat of cottonseeds. In this study, we reported a new fuzzless-tufted cotton mutant (Gossypium hirsutum) and showed that fuzzless-tufted near-isogenic lines (NILs) had similar agronomic traits and a higher ginning efficiency compared to their recurrent parents with normal fuzzy seeds. Genetic analysis revealed that the mutant phenotype is determined by a single incomplete dominant locus, designated N5. The mutation was fine mapped to an approximately 250-kb interval containing 33 annotated genes using a combination of bulked segregant sequencing, SNP chip genotyping, and fine mapping. Comparative transcriptomic analysis using 0–6 days post-anthesis (dpa) ovules from NILs segregating for the phenotypes of fuzzless-tufted (mutant) and normal fuzzy cottonseeds (wild-type) uncovered candidate genes responsible for the mutant phenotype. It also revealed that the flanking region of the N5 locus is enriched with differentially expressed genes (DEGs) between the mutant and wild-type. Several of those DEGs are members of the gene families with demonstrated roles in cell initiation and elongation, such as calcium-dependent protein kinase and expansin. The transcriptome landscape of the mutant was significantly reprogrammed in the 6 dpa ovules and, to a less extent, in the 0 dpa ovules, but not in the 2 and 4 dpa ovules. At both 0 and 6 dpa, the reprogrammed mutant transcriptome was mainly associated with cell wall modifications and transmembrane transportation, while transcription factor activity was significantly altered in the 6 dpa mutant ovules. These results imply a similar molecular basis for initiation of lint and fuzz fibers despite certain differences.

New horizons in mitochondrial contact site research

2020 ◽  
Vol 401 (6-7) ◽  
pp. 793-809
Author(s):  
Naama Zung ◽  
Maya Schuldiner
Keyword(s):  
Endoplasmic Reticulum ◽  
Molecular Mechanisms ◽  
Contact Site ◽  
New Horizons ◽  
Contact Sites ◽  
Future Goals ◽  
Close Proximity ◽  
Recent Developments ◽  
Site Field ◽  
First Contact

AbstractContact sites, areas where two organelles are held in close proximity through the action of molecular tethers, enable non-vesicular communication between compartments. Mitochondria have been center stage in the contact site field since the discovery of the first contact between mitochondria and the endoplasmic reticulum (ER) over 60 years ago. However, only now, in the last decade, has there been a burst of discoveries regarding contact site biology in general and mitochondrial contacts specifically. The number and types of characterized contacts increased dramatically, new molecular mechanisms enabling contact formation were discovered, additional unexpected functions for contacts were shown, and their roles in cellular and organismal physiology were emphasized. Here, we focus on mitochondria as we highlight the most recent developments, future goals and unresolved questions in the field.

scholarly journals Molecular Mechanisms of Drug Resistance in Glioblastoma

2021 ◽  
Vol 22 (12) ◽  
pp. 6385
Author(s):  
Maya A. Dymova ◽  
Elena V. Kuligina ◽  
Vladimir A. Richter
Keyword(s):  
Drug Resistance ◽  
Brain Tumor ◽  
Molecular Mechanisms ◽  
Primary Brain Tumor ◽  
Therapeutic Resistance ◽  
Molecular Characteristics ◽  
Blood Brain ◽  
Conventional Radiation ◽  
The Brain ◽  
Made In

Glioblastoma multiforme (GBM) is the most common and fatal primary brain tumor, is highly resistant to conventional radiation and chemotherapy, and is not amenable to effective surgical resection. The present review summarizes recent advances in our understanding of the molecular mechanisms of therapeutic resistance of GBM to already known drugs, the molecular characteristics of glioblastoma cells, and the barriers in the brain that underlie drug resistance. We also discuss the progress that has been made in the development of new targeted drugs for glioblastoma, as well as advances in drug delivery across the blood–brain barrier (BBB) and blood–brain tumor barrier (BBTB).

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