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Gordon V.,Cancer Care Manitoba | Gordon V.,University of Manitoba | Banerji S.,Cancer Care Manitoba | Banerji S.,University of Manitoba | Banerji S.,Manitoba Institute of Cell Biology
Clinical Cancer Research | Year: 2013

The triple-negative breast cancer (TNBC) subtype, defined clinically by the lack of estrogen, progesterone, and Her2 receptor expression, accounts for 10% to 15% of annual breast cancer diagnoses. Currently, limited therapeutic options have shown clinical benefit beyond cytotoxic chemotherapy. Defining this clinical cohort and identifying subtype-specific molecular targets remain critical for new therapeutic development. The current era of high-throughput molecular analysis has revealed new insights into these targets and confirmed the phosphoinositide 3-kinase (PI3K) as a key player in pathogenesis. The improved knowledge of the molecular basis of TNBC in parallel with efforts to develop new PI3K pathway-specific inhibitors may finally produce the therapeutic breakthrough that is desperately needed. © 2013 American Association for Cancer Research.


Amrein L.,Lady Davis Institute for Medical Research | Soulieres D.,Center Hospitalier Of Luniversite Of Montreal | Johnston J.B.,Manitoba Institute of Cell Biology | Aloyz R.,Lady Davis Institute for Medical Research
Leukemia Research | Year: 2011

B-cell chronic lymphocytic leukemia (CLL) is the most common leukemia in adults and there is no cure for the disease. Although dasatinib is cytotoxic to primary CLL lymphocytes in vitro, the drug has been shown to be active in a small percent of CLL patients. Our previous results suggest that dasatinib targets del17 CLL lymphocytes which are the CLL patients with the worst prognosis. Here we present mechanistic evidence that dasatinib induces endoplasmic reticulum stress and autophagy in CLL lymphocytes. Furthermore we provide evidence suggesting that autophagy mediates resistance to the drugs, process that is modulated by p53. © 2010 Elsevier Ltd.


Choi Y.J.,University of California at Berkeley | Lin C.-P.,University of California at Berkeley | Ho J.J.,University of California at Berkeley | He X.,40 Landsdowne Street | And 10 more authors.
Nature Cell Biology | Year: 2011

Somatic reprogramming induced by defined transcription factors is a low-efficiency process that is enhanced by p53 deficiency. So far, p21 is the only p53 target shown to contribute to p53 repression of iPSC (induced pluripotent stem cell) generation, indicating that additional p53 targets may regulate this process. Here, we demonstrate that miR-34 microRNAs (miRNAs), particularly miR-34a, exhibit p53-dependent induction during reprogramming. Mir34a deficiency in mice significantly increased reprogramming efficiency and kinetics, with miR-34a and p21 cooperatively regulating somatic reprogramming downstream of p53. Unlike p53 deficiency, which enhances reprogramming at the expense of iPSC pluripotency, genetic ablation of Mir34a promoted iPSC generation without compromising self-renewal or differentiation. Suppression of reprogramming by miR-34a was due, at least in part, to repression of pluripotency genes, including Nanog, Sox2 and Mycn (also known as N-Myc). This post-transcriptional gene repression by miR-34a also regulated iPSC differentiation kinetics. miR-34b and c similarly repressed reprogramming; and all three miR-34 miRNAs acted cooperatively in this process. Taken together, our findings identified miR-34 miRNAs as p53 targets that play an essential role in restraining somatic reprogramming. © 2011 Macmillan Publishers Limited. All rights reserved.


Ghavami S.,Manitoba Institute of Cell Biology | Ghavami S.,University of Manitoba | Eshragi M.,Manitoba Institute of Cell Biology | Ande S.R.,Manitoba Institute of Cell Biology | And 7 more authors.
Cell Research | Year: 2010

The complex formed by two members of the S100 calcium-binding protein family, S100A8/A9, exerts apoptosis-inducing activity in various cells of different origins. Here, we present evidence that the underlying molecular mechanisms involve both programmed cell death I (PCD I, apoptosis) and PCD II (autophagy)-like death. Treatment of cells with S100A8/A9 caused the increase of Beclin-1 expression as well as Atg12-Atg5 formation. S100A8/A9-induced cell death was partially inhibited by the specific PI3-kinase class III inhibitor, 3-methyladenine (3-MA), and by the vacuole H +-ATPase inhibitor, bafilomycin-A1 (Baf-A1). S100A8/A9 provoked the translocation of BNIP3, a BH3 only pro-apoptotic Bcl2 family member, to mitochondria. Consistent with this finding, ΔTM-BNIP3 overexpression partially inhibited S100A8/A9-induced cell death, decreased reactive oxygen species (ROS) generation, and partially protected against the decrease in mitochondrial transmembrane potential in S100A8/A9-treated cells. In addition, either ΔTM-BNIP3 overexpression or N-acetyl-L-cysteine co-treatment decreased lysosomal activation in cells treated with S100A8/A9. Our data indicate that S100A8/A9-promoted cell death occurs through the cross-talk of mitochondria and lysosomes via ROS and the process involves BNIP3. © 2010 IBCB, SIBS, CAS All rights reserved.


Yoon J.-Y.,University of Manitoba | Yoon J.-Y.,Manitoba Institute of Cell Biology | Ishdorj G.,Manitoba Institute of Cell Biology | Graham B.A.,Manitoba Institute of Cell Biology | And 2 more authors.
Apoptosis | Year: 2014

Histone deacetylase (HDAC) inhibitors have been shown synergize with a number of cytotoxic drugs in leukemic cells. In chronic lymphocytic leukemia (CLL), the first line therapy is based on the combination of fludarabine, a nucleoside analogue, and rituximab, an anti- CD20 monoclonal antibody, and there are presently no HDAC inhibitors are used to manage CLL. In the present study, we found that the addition of valproic acid (VPA), a HDAC inhibitor, increases cell death in B-cell-neoplasmderived cell lines, BJAB, NALM-6 and I-83. This increased apoptosis caused release of mitochondrial cytochrome c, activation of caspases, and increased reactive oxygen species (ROS). The addition of a ROS scavenger inhibited cell death induced by the VPA-fludarabine combination. In contrast, blocking the death receptor pathway failed to inhibit VPA increased fludarabine induced apoptosis. Combination of VPA and fludarabine treatment decreased both total and phosphorylated levels of AKT, an important anti-Apoptotic protein, and ATM, a pivotal protein in DNA damage response. Chemical inhibition of AKT or ATM was sufficient to enhance fludarabine- induced apoptosis. We next examined patient samples from a local clinical trial where relapsed CLL patients were treated with VPA and examined the effects of VPA on AKT and ATM in vivo. After 30 days, there was a reduction in ATM levels in three out of the four patients treated, while AKT phosphorylation was reduced only in one patient. Taken together, VPA reduces ATM levels, thereby increasing ROS-dependent cell death via the mitochondrial apoptotic pathway when combined with fludarabine. © Springer Science+Business Media New York 2013.


Lin C.-P.,University of California at Berkeley | Choi Y.J.,University of California at Berkeley | Hicks G.G.,Manitoba Institute of Cell Biology | He L.,University of California at Berkeley
Cell Cycle | Year: 2012

The p53 pathway plays an essential role in tumor suppression, regulating multiple cellular processes coordinately to maintain genome integrity in both somatic cells and stem cells. Despite decades of research dedicated to p53 function in differentiated somatic cells, we are just starting to understand the complexity of the p53 pathway in the biology of pluripotent stem cells and tissue stem cells. Recent studies have demonstrated that p53 suppresses proliferation, promotes differentiation of embryonic stem (ES) cells and constitutes an important barrier to somatic reprogramming. In addition, emerging evidence reveals the role of the p53 network in the self-renewal, proliferation and genomic integrity of adult stem cells. Interestingly, non-coding RNAs and microRNAs in particular, are integral components of the p53 network, regulating multiple p53-controlled biological processes to modulate the self-renewal and differentiation potential of a variety of stem cells. Thus, elucidation of the p53-miRNA axis in stem cell biology may generate profound insights into the mechanistic overlap between malignant transformation and stem cell biology. © 2012 Landes Bioscience.


Ishdorj G.,Manitoba Institute of Cell Biology | Li L.,Manitoba Institute of Cell Biology | Li L.,University of Manitoba | Gibson S.B.,Manitoba Institute of Cell Biology | Gibson S.B.,University of Manitoba
Leukemia and Lymphoma | Year: 2012

Hematological malignancies are characterized by the accumulation of lymphoid and myeloid cell types due to selective proliferation and survival in blood, bone marrow and lymph nodes. Treatments of hematological malignancies are often effective but eventually relapse, and drug resistance occurs. A better understanding of the mechanism of action of both chemotherapeutic drugs and drug resistance is required. Autophagy has been shown to regulate both cell survival and cell death, leading to both cancer development and tumor suppression. In addition, many chemotherapeutic drugs induce autophagy, leading to either drug resistance or cell death. Autophagy is regulated by signaling pathways such as p53 and by the production of reactive oxygen species (ROS). This review focuses on the regulation of autophagy in human hematologic malignancy leading to either cell survival or death. In addition, the role that ROS play in regulating autophagy and its implication for hematological cancers is discussed. © 2011 Informa UK, Ltd.


Ishdorj G.,Manitoba Institute of Cell Biology | Ishdorj G.,University of Manitoba | Johnston J.B.,Manitoba Institute of Cell Biology | Johnston J.B.,University of Manitoba | And 2 more authors.
Molecular Cancer Therapeutics | Year: 2010

Phosphorylation of STAT3 on serine 727 regulates gene expression and is found to be elevated in many Bleukemia cells including chronic lymphocytic leukemia (CLL). It is, however, unclear whether targeting STAT3 will be an effective antileukemia therapy. In this study, we assessed in vitro antileukemia activity of the STAT3 inhibitor JSI-124 (cucurbitacin I). JSI-124 potently induces apoptosis in 3 B-leukemia cell lines (BJAB, I-83, and NALM-6) andin primaryCLLcells andwasassociated with a reduction in serine 727phosphorylation ofSTAT3. Similarly, knockdown ofSTAT3 expression induced apoptosis in these leukemiacells. Inaddition,wefoundthat JSI-124 and knockdown of STAT3 decreased antiapoptotic protein XIAP expression and overexpression of XIAP blocked JSI-124-induced apoptosis. Furthermore, we found that combined treatment of JSI-124 and TRAIL increased apoptosis associated with an increase in death receptor 4 expression. Besides apoptosis, we found that JSI-124 also induced cell-cycle arrest prior to apoptosis in B-leukemia cells. This corresponded with reduced expression of the cell-cycle regulatory gene, cdc-2. Thus, we present here for the first time that JSI-124 induced suppression of serine 727 phosphorylation of STAT3, leading to apoptosis and cell-cycle arrest through alterations in gene transcription in B-leukemia cells. © 2010 AACR.


Gibson S.B.,Manitoba Institute of Cell Biology | Gibson S.B.,University of Manitoba
Journal of Pathology | Year: 2012

Autophagy contributes to cell survival and is up-regulated under hypoxia in many different cancers. Ovarian cancer has a poor prognosis and is generally resistant to chemotherapy. Through genetic profiling, it has becoming evident that ovarian cancer has distinct subtypes but the significance of these subtypes in ovarian cancer remains unclear. In this issue, Dr Lum and colleagues have presented evidence that autophagy as measured by LC3A staining occurs in a clear cell ovarian cancer that is correlated with hypoxic regions and poor overall survival. In addition, autophagy under hypoxia appears to be higher in clear cell ovarian cancer cells compared to other subtypes. This indicates that autophagy could be a factor in drug resistance and poor survival in clear cell ovarian cancer patients. This insight could lead to a better understanding of the role of autophagy under hypoxia in human ovarian cancer and could be a valuable biomarker for the development of better therapies for clear cell ovarian cancers. Copyright © 2012 Pathological Society of Great Britain and Ireland.


Lu P.,University of Manitoba | Kamboj A.,University of Manitoba | Gibson S.B.,Manitoba Institute of Cell Biology | Anderson C.M.,University of Manitoba
Journal of Neuroscience | Year: 2014

Excessive pathophysiological activity of the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP1) causes neuron death in brain hypoxia/ischemia by inducing mitochondrial permeability transition and nuclear translocation of apoptosis-inducing factor (AIF). Bcl-2/adenovirus E1B19 kDa-interacting protein (Bnip3) is aprodeath BH3-only Bcl-2 protein family member that is induced in hypoxia, and has effects on mitochondrial permeability and neuronal survival similar to those caused by PARP1 activation. We hypothesized that Bnip3 is a critical mediator of PARP1-induced mitochondrial dysfunction and neuron death. Hypoxic death of mouse cortical neuron cultures was mitigated by deletion of either PARP1 or Bnip3, indicating that both factors are involved. Direct normoxic PARP1 activation by a DNA alkylating agent enhanced Bnip3 expression, and caused Bnip3-dependent mitochondrial membrane permeability, AIF translocation, and neuron death. Hypoxia produced PARP1-dependent depletion of nicotinamide adenine dinucleotide (NAD+) and inhibition of the NAD+-dependent class III histone deactelyase (HDAC) sirtuin-1 (SIRT1). This, in turn, led to hyperacetylation and nuclear localization of the forkhead box (Fox) protein FoxO3a, followed by enhanced association of FoxO3a with the Bnip3 upstream promoter region, increased levels of Bnip3 transcript, and elevated mitochondrial Bnip3 immunoreactivity. Finally, FoxO3a silencing using a lentiviral short hairpin RNA approach significantly reduced hypoxic Bnip3 expression, mitochondrial damage, and neuron death. Together, these data illustrate a direct PARP1-mediated hypoxic signaling pathway involving NAD+ depletion, SIRT1 inhibition, FoxO3a-driven Bnip3 generation, and mitochondrial AIF release. ©2014 the authors.

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