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Papers by Katarzyna Mnich

Seminars in cancer biology, Jan 23, 2015

Cancer cells are exposed to intrinsic (oncogene) or extrinsic (microenvironmental) challenges, le... more Cancer cells are exposed to intrinsic (oncogene) or extrinsic (microenvironmental) challenges, leading to activation of stress response pathways. The unfolded protein response (UPR) is the cellular response to endoplasmic reticulum (ER) stress and plays a pivotal role in tumor development. Depending on ER stress intensity and duration, the UPR is either pro-survival to preserve ER homeostasis or pro-death if the stress cannot be resolved. On one hand, the adaptive arm of the UPR is essential for cancer cells to survive the harsh conditions they are facing, and on the other hand, cancer cells have evolved mechanisms to bypass ER stress-induced cell death, thereby conferring them with a selective advantage for malignant transformation. Therefore, the mechanisms involved in the balance between survival and death outcomes of the UPR may be exploited as therapeutic tools to treat cancer.

FEBS open bio, 2014

A mild heat shock (HS) preconditioning and acquisition of thermotolerance protects cells against ... more A mild heat shock (HS) preconditioning and acquisition of thermotolerance protects cells against a variety of cytotoxic agents that otherwise induce apoptosis. Here we tested whether there is a molecular link between HS preconditioning and endoplasmic reticulum (ER) stress-induced apoptosis. ER stress results from a loss of ER lumen homeostasis, culminating in an accumulation of unfolded/misfolded proteins in the ER and activation of unfolded protein response (UPR). Unresolved, ER stress leads to activation of BH3-only proteins, mitochondrial membrane permeabilization, caspase activation and apoptotic cell death. HS preconditioning (1 h at 42 °C) induced a rapid increase in HSPA1 (HSP70) levels which remained elevated for at least 48 h post-HS. HS preconditioning significantly reduced BAX, caspase activation and apoptosis in cell cultures treated with the ER stress-inducing agents thapsigargin (TG) and tunicamycin (TM). HS-mediated protection was found to be due to regulation of the...

International journal of cell biology, 2010

6-hydroxydopamine (6-OHDA) is a selective neurotoxin that is widely used to investigate cell deat... more 6-hydroxydopamine (6-OHDA) is a selective neurotoxin that is widely used to investigate cell death and protective strategies in models of Parkinson's disease. Here, we investigated the effects of the endogenous cannabinoid, anandamide, on 6-OHDA-induced toxicity in rat adrenal phaeochromocytoma PC12 cells. Morphological analysis and caspase-3 activity assay revealed that anandamide inhibited 6-OHDA-induced apoptosis. The protection was not affected by antagonists of either cannabinoid receptors (CB(1) or CB(2)) or the vanilloid receptor TRPV1. Anandamide-dependent protection was reduced by pretreatment with LY294002 (inhibitor of phosphatidylinositol 3-kinase, PI3K) and unaffected by U0126 (inhibitor of extracellularly-regulated kinase). Interestingly, phosphorylation of c-Jun-NH2-terminal kinase (JNK) in cells exposed to 6-OHDA was strongly reduced by anandamide pre-treatment. Furthermore, 6-OHDA induced c-Jun activation and increased Bim expression, both of which were inhibite...

Brain Research Bulletin, 2010

The endocannabinoid system is emerging as a potential alternative to the dopaminergic system for ... more The endocannabinoid system is emerging as a potential alternative to the dopaminergic system for the treatment of Parkinson's disease. Like all emerging targets, validation of this system's potential for treating human Parkinsonism necessitates testing in animal models of the condition. However, if components of the endocannabinoid system are altered by the induction of a Parkinsonian state in animal models, this could have an impact on the interpretation of such preclinical experiments. This study sought to determine if expression of the CB 1 subtype of cannabinoid receptor is altered in the two most commonly used rat models of Parkinson's disease. Parkinsonian lesions were induced by stereotaxic injection of 6-hydroxydopamine into the axons (medial forebrain bundle) or terminals (striatum) of the nigrostriatal pathway. On days 1, 3, 7, 14 and 28 post-lesion, rats were sacrificed and brains were processed for tyrosine hydroxylase and CB 1 receptor immunohistochemistry. The CB 1 receptor was expressed strongly in the substantia nigra pars reticulata, minimally overlapping with tyrosine hydroxylase immunoreactivity in the pars compacta. Interestingly, while there was little change in CB 1 receptor expression following axonal lesion, expression of the receptor was significantly reduced following terminal lesion. Loss of CB 1 receptor expression in the pars reticulata correlated significantly with the loss of striatal and nigral volume after terminal lesion indicating this may have been due to 6-hydroxydopamineinduced non-specific damage of striatonigral neurons which are known to express CB 1 receptors. Thus, this result has implications for the choice of model and interpretation of studies used to investigate potential cannabinoid-based therapies for Parkinson's disease as well as striatonigral diseases such as Huntington's disease and Multiple Systems Atrophy.

Cell death & disease, 2014

Nerve growth factor (NGF) is well characterised as an important pro-survival factor in neuronal c... more Nerve growth factor (NGF) is well characterised as an important pro-survival factor in neuronal cells that can inhibit apoptotic cell death upstream of mitochondrial outer membrane permeabilisation. Here we addressed the question of whether NGF can also protect against apoptosis downstream of caspase activation. NGF treatment promoted a rapid reduction in the level of the p17 subunit of active caspase-3 in PC12 cells that had been induced to undergo apoptosis by various cytotoxins. The mechanism involved TrkA-dependent activation of extracellular signal-regulated kinase (ERK1/2) but not phosphatidylinositol 3-kinase (PI3K)/Akt, and de novo protein synthesis. Involvement of inhibitor of apoptosis proteins (IAPs) and proteasomal degradation were ruled out. In contrast, inhibition of lysosome function using chloroquine and concanamycin A reversed NGF-induced removal of p17. Moreover, in NGF-treated cells, active caspases were found to be localised to lysosomes. The involvement of macroautophagy and chaperone-mediated autophagy were ruled out. Taken together, these findings suggest an anti-apoptotic mechanism by which NGF induces removal of active caspase-3 in a lysosome-dependent manner.

Seminars in cancer biology, Jan 23, 2015

Cancer cells are exposed to intrinsic (oncogene) or extrinsic (microenvironmental) challenges, le... more Cancer cells are exposed to intrinsic (oncogene) or extrinsic (microenvironmental) challenges, leading to activation of stress response pathways. The unfolded protein response (UPR) is the cellular response to endoplasmic reticulum (ER) stress and plays a pivotal role in tumor development. Depending on ER stress intensity and duration, the UPR is either pro-survival to preserve ER homeostasis or pro-death if the stress cannot be resolved. On one hand, the adaptive arm of the UPR is essential for cancer cells to survive the harsh conditions they are facing, and on the other hand, cancer cells have evolved mechanisms to bypass ER stress-induced cell death, thereby conferring them with a selective advantage for malignant transformation. Therefore, the mechanisms involved in the balance between survival and death outcomes of the UPR may be exploited as therapeutic tools to treat cancer.

FEBS open bio, 2014

A mild heat shock (HS) preconditioning and acquisition of thermotolerance protects cells against ... more A mild heat shock (HS) preconditioning and acquisition of thermotolerance protects cells against a variety of cytotoxic agents that otherwise induce apoptosis. Here we tested whether there is a molecular link between HS preconditioning and endoplasmic reticulum (ER) stress-induced apoptosis. ER stress results from a loss of ER lumen homeostasis, culminating in an accumulation of unfolded/misfolded proteins in the ER and activation of unfolded protein response (UPR). Unresolved, ER stress leads to activation of BH3-only proteins, mitochondrial membrane permeabilization, caspase activation and apoptotic cell death. HS preconditioning (1 h at 42 °C) induced a rapid increase in HSPA1 (HSP70) levels which remained elevated for at least 48 h post-HS. HS preconditioning significantly reduced BAX, caspase activation and apoptosis in cell cultures treated with the ER stress-inducing agents thapsigargin (TG) and tunicamycin (TM). HS-mediated protection was found to be due to regulation of the...

International journal of cell biology, 2010

6-hydroxydopamine (6-OHDA) is a selective neurotoxin that is widely used to investigate cell deat... more 6-hydroxydopamine (6-OHDA) is a selective neurotoxin that is widely used to investigate cell death and protective strategies in models of Parkinson's disease. Here, we investigated the effects of the endogenous cannabinoid, anandamide, on 6-OHDA-induced toxicity in rat adrenal phaeochromocytoma PC12 cells. Morphological analysis and caspase-3 activity assay revealed that anandamide inhibited 6-OHDA-induced apoptosis. The protection was not affected by antagonists of either cannabinoid receptors (CB(1) or CB(2)) or the vanilloid receptor TRPV1. Anandamide-dependent protection was reduced by pretreatment with LY294002 (inhibitor of phosphatidylinositol 3-kinase, PI3K) and unaffected by U0126 (inhibitor of extracellularly-regulated kinase). Interestingly, phosphorylation of c-Jun-NH2-terminal kinase (JNK) in cells exposed to 6-OHDA was strongly reduced by anandamide pre-treatment. Furthermore, 6-OHDA induced c-Jun activation and increased Bim expression, both of which were inhibite...

Brain Research Bulletin, 2010

The endocannabinoid system is emerging as a potential alternative to the dopaminergic system for ... more The endocannabinoid system is emerging as a potential alternative to the dopaminergic system for the treatment of Parkinson's disease. Like all emerging targets, validation of this system's potential for treating human Parkinsonism necessitates testing in animal models of the condition. However, if components of the endocannabinoid system are altered by the induction of a Parkinsonian state in animal models, this could have an impact on the interpretation of such preclinical experiments. This study sought to determine if expression of the CB 1 subtype of cannabinoid receptor is altered in the two most commonly used rat models of Parkinson's disease. Parkinsonian lesions were induced by stereotaxic injection of 6-hydroxydopamine into the axons (medial forebrain bundle) or terminals (striatum) of the nigrostriatal pathway. On days 1, 3, 7, 14 and 28 post-lesion, rats were sacrificed and brains were processed for tyrosine hydroxylase and CB 1 receptor immunohistochemistry. The CB 1 receptor was expressed strongly in the substantia nigra pars reticulata, minimally overlapping with tyrosine hydroxylase immunoreactivity in the pars compacta. Interestingly, while there was little change in CB 1 receptor expression following axonal lesion, expression of the receptor was significantly reduced following terminal lesion. Loss of CB 1 receptor expression in the pars reticulata correlated significantly with the loss of striatal and nigral volume after terminal lesion indicating this may have been due to 6-hydroxydopamineinduced non-specific damage of striatonigral neurons which are known to express CB 1 receptors. Thus, this result has implications for the choice of model and interpretation of studies used to investigate potential cannabinoid-based therapies for Parkinson's disease as well as striatonigral diseases such as Huntington's disease and Multiple Systems Atrophy.

Cell death & disease, 2014

Nerve growth factor (NGF) is well characterised as an important pro-survival factor in neuronal c... more Nerve growth factor (NGF) is well characterised as an important pro-survival factor in neuronal cells that can inhibit apoptotic cell death upstream of mitochondrial outer membrane permeabilisation. Here we addressed the question of whether NGF can also protect against apoptosis downstream of caspase activation. NGF treatment promoted a rapid reduction in the level of the p17 subunit of active caspase-3 in PC12 cells that had been induced to undergo apoptosis by various cytotoxins. The mechanism involved TrkA-dependent activation of extracellular signal-regulated kinase (ERK1/2) but not phosphatidylinositol 3-kinase (PI3K)/Akt, and de novo protein synthesis. Involvement of inhibitor of apoptosis proteins (IAPs) and proteasomal degradation were ruled out. In contrast, inhibition of lysosome function using chloroquine and concanamycin A reversed NGF-induced removal of p17. Moreover, in NGF-treated cells, active caspases were found to be localised to lysosomes. The involvement of macroautophagy and chaperone-mediated autophagy were ruled out. Taken together, these findings suggest an anti-apoptotic mechanism by which NGF induces removal of active caspase-3 in a lysosome-dependent manner.