The Raf/MEK/ERK signal transduction cascade as a target for chemotherapeutic intervention in leukemia

Jt, Lee; McCubrey, JA

doi:10.1038/sj.leu.2402460

Cited by 208 publications

(18 citation statements)

References 346 publications

(339 reference statements)

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“…Notably, genetic or pharmacologic interruption of these pathways significantly attenuated ricolinostat/CFZ lethality, arguing for functional roles for these stress kinases in the pathways leading to cell death. In contrast, enforced activation of ERK1/2, which generally inhibits apoptosis (46), failed to diminish ricolinostat/CFZ lethality, suggesting that ERK1/2 inactivation represents a secondary event. It is noteworthy that combined ricolinostat/CFZ triggered marked oxidative injury (e.g., ROS generation), which played an important functional role in cell death.…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Interactions between the HDAC6 Inhibitor Ricolinostat (ACY1215) and the Irreversible Proteasome Inhibitor Carfilzomib in Non-Hodgkin Lymphoma Cells

Dasmahapatra

Patel

Friedberg

et al. 2014

Molecular Cancer Therapeutics

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Interactions between the HDAC6 inhibitor ricolinostat (ACY1215) and the irreversible proteasome inhibitor Carfilzomib (CFZ) were examined in non-Hodgkin’s lymphoma models, including diffuse large B-cell (DLBCL), mantle cell (MCL) and double-hit lymphoma cells. Marked in vitro synergism was observed in multiple cell types associated with activation of cellular stress pathways (e.g., JNK1/2, ERK1/2, and p38) accompanied by increases in DNA damage (γH2A.X), G2M arrest, and the pronounced induction of mitochondrial injury and apoptosis. Combination treatment with CFZ and ricolinostat increased reactive oxygen species (ROS), while the antioxidant TBAP attenuated DNA damage, JNK activation, and cell death. Similar interactions occurred in bortezomib-resistant and double-hit DLBCL, MCL, and primary DLBCL cells, but not in normal CD34+ cells. However, ricolinostat did not potentiate inhibition of chymotryptic activity by CFZ. shRNA knock-down of JNK1 (but not MEK1/2), or pharmacologic inhibition of p38, significantly reduced CFZ/ricolinostat lethality, indicating a functional contribution of these stress pathways to apoptosis. Combined exposure to CFZ and ricolinostat also markedly down-regulated the cargo-loading protein HR23B. Moreover, HR23B knock-down significantly increased CFZ- and ricolinostat-mediated lethality, suggesting a role for this event in cell death. Finally, combined in vivo treatment with CFZ and ricolinostat was well tolerated and significantly suppressed tumor growth and increased survival in an MCL xenograft model. Collectively, these findings indicate that CFZ and ricolinostat interact synergistically in NHL cells through multiple stress-related mechanisms, and suggest that this strategy warrants further consideration in NHL.

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Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Interactions between the HDAC6 Inhibitor Ricolinostat (ACY1215) and the Irreversible Proteasome Inhibitor Carfilzomib in Non-Hodgkin Lymphoma Cells

Dasmahapatra

Patel

Friedberg

et al. 2014

Molecular Cancer Therapeutics

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“…Akt, an important and probably essential downstream component of PI3K-mediated oncogenic signaling, provides a critical cell survival signal for tumor progression by phosphorylating proteins involved in cell cycle regulation and proapoptotic factors [8, 39]. The MAPK signaling pathway has been shown to be activated in response to certain chemotherapeutic drugs [40]. In the present study, the roles of Akt, MAPK, and its downstream transcription factor NF- κ B in regulating IK-induced apoptosis were examined in primary and metastatic OSCCs.…”

Section: Discussionmentioning

confidence: 99%

Isocudraxanthone K Induces Growth Inhibition and Apoptosis in Oral Cancer Cells via Hypoxia Inducible Factor-1α

Shin

Lee

Kang

et al. 2014

BioMed Research International

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Isocudraxanthone K (IK) is a novel, natural compound from a methanol extract of the root bark of Cudrania tricuspidata. It has not been shown previously that IK possessed antitumor activity. We investigated the antitumor effects and molecular mechanism of IK and related signal transduction pathway(s) in oral squamous cell carcinoma cells (OSCCCs). The MTT assay revealed that IK had an antiproliferative effect on OSCCCs, in a dose- and time-dependent manner. IK induced apoptosis in OSCCCs, as identified by a cell-cycle analysis, annexin V-FITC and propidium iodide staining, and the nuclear morphology in cell death. IK caused time-dependent phosphorylation of Akt, p38, and ERK (extracellular signal-regulated kinase). In addition, IK increased the cytosolic to nuclear translocation of nuclear factor-κB (NF-κB) p65 and the degradation and phosphorylation of IκB-α in HN4 and HN12 cells. Furthermore, IK treatment downregulated hypoxia-inducible factor 1α (HIF-1α) and its target gene, vascular endothelial growth factor (VEGF). Cobalt chloride (CoCl2), a HIF-1α activator, attenuated the IK-induced growth-inhibiting and apoptosis-inducing effects, and blocked IK-induced expression of apoptosis regulatory proteins, such as Bax, Bcl-2, caspase-3, caspase-8, and caspase-9, and cytochrome c. Collectively, these data provide the first evidence of antiproliferative and apoptosis-inducing effects of IK as a HIF-1α inhibitor and suggest it may be a drug candidate for chemotherapy against oral cancer.

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“…This observation can be rationalized by the fact that some of the major pathways involved in cell migration (e.g. PI3K/Akt and Raf/MEK/ERK), are also important for survival and proliferation signaling [13]. However, little is known regarding the extent to which there is overlap or divergence of the upstream and downstream effectors of these pathways in the context of migration versus survival/proliferation.…”

Section: Resultsmentioning

confidence: 99%

Elucidating the CXCL12/CXCR4 Signaling Network in Chronic Lymphocytic Leukemia through Phosphoproteomics Analysis

et al. 2010

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BackgroundChronic Lymphocytic Leukemia (CLL) pathogenesis has been linked to the prolonged survival and/or apoptotic resistance of leukemic B cells in vivo, and is thought to be due to enhanced survival signaling responses to environmental factors that protect CLL cells from spontaneous and chemotherapy-induced death. Although normally associated with cell migration, the chemokine, CXCL12, is one of the factors known to support the survival of CLL cells. Thus, the signaling pathways activated by CXCL12 and its receptor, CXCR4, were investigated as components of these pathways and may represent targets that if inhibited, could render resistant CLL cells more susceptible to chemotherapy.Methodology/Principal FindingsTo determine the downstream signaling targets that contribute to the survival effects of CXCL12 in CLL, we took a phosphoproteomics approach to identify and compare phosphopeptides in unstimulated and CXCL12-stimulated primary CLL cells. While some of the survival pathways activated by CXCL12 in CLL are known, including Akt and ERK1/2, this approach enabled the identification of additional signaling targets and novel phosphoproteins that could have implications in CLL disease and therapy. In addition to the phosphoproteomics results, we provide evidence from western blot validation that the tumor suppressor, programmed cell death factor 4 (PDCD4), is a previously unidentified phosphorylation target of CXCL12 signaling in all CLL cells probed. Additionally, heat shock protein 27 (HSP27), which mediates anti-apoptotic signaling and has previously been linked to chemotherapeutic resistance, was detected in a subset (∼25%) of CLL patients cells examined.Conclusions/SignificanceSince PDCD4 and HSP27 have previously been associated with cancer and regulation of cell growth and apoptosis, these proteins may have novel implications in CLL cell survival and represent potential therapeutic targets. PDCD4 also represents a previously unknown signaling target of chemokine receptors; therefore, these observations increase our understanding of alternative pathways to migration that may be activated or inhibited by chemokines in the context of cancer cell survival.

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The Raf/MEK/ERK signal transduction cascade as a target for chemotherapeutic intervention in leukemia

Cited by 208 publications

References 346 publications

In Vitro and In Vivo Interactions between the HDAC6 Inhibitor Ricolinostat (ACY1215) and the Irreversible Proteasome Inhibitor Carfilzomib in Non-Hodgkin Lymphoma Cells

In Vitro and In Vivo Interactions between the HDAC6 Inhibitor Ricolinostat (ACY1215) and the Irreversible Proteasome Inhibitor Carfilzomib in Non-Hodgkin Lymphoma Cells

Isocudraxanthone K Induces Growth Inhibition and Apoptosis in Oral Cancer Cells via Hypoxia Inducible Factor-1α

Elucidating the CXCL12/CXCR4 Signaling Network in Chronic Lymphocytic Leukemia through Phosphoproteomics Analysis

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