Mitogen-activated protein kinase inhibitors differently affect the growth inhibition and death of a proteasome inhibitor, MG132-treated human pulmonary fibroblast cells

2011 ◽  
Vol 30 (12) ◽  
pp. 1945-1954 ◽  
Author(s):  
Woo Hyun Park
Keyword(s):  
Cell Death ◽  
Cell Growth ◽  
Growth Inhibition ◽  
Proteasome Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Cell Growth Inhibition ◽  
P38 Inhibitor ◽  
Mitogen Activated Protein ◽  
Mapk Inhibitors ◽  
Pulmonary Fibroblast

Carbobenzoxy-Leu-Leu-leucinal (MG132) as a proteasome inhibitor can induce growth inhibition and death in lung cancer or normal cells. However, little is known about relationship between proteasome inhibition and mitogen-activated protein kinase (MAPK) signaling in normal lung cells. Thus, in the present study, we investigated the effects of MAPK inhibitors on MG132-treated human pulmonary fibroblast (HPF) cells in relation to cell growth inhibition, cell death, reactive oxygen species (ROS) and glutathione (GSH). Treatment with 15 μM MG132 increased ROS levels including mitochondrial O2•− and GSH depleted cell numbers in HPF cells at 24 hours. MAP kinase or ERK kinase (MEK) inhibitor did not significantly affect cell growth inhibition, cell death, the loss of mitochondrial membrane potential (MMP; Δ Ψm), ROS level and GSH depletion in MG132-treated HPF cells. c-Jun N-terminal kinase (JNK) inhibitor attenuated the growth inhibition and death by MG132. This inhibitor also significantly decreased O2•− level in MG132-treated HPF cells. Although p38 inhibitor slightly enhanced HPF cell growth inhibition by MG132, this inhibitor and siRNA prevented HPF cell death induced by MG132. p38 inhibitor also attenuated d O2•− level and GSH depletion. Moreover, extracellular signal regulated kinase (ERK), JNK or p38 siRNA did not strongly affect ROS levels in MG132-treated HPF cells. ERK and JNK siRNAs decreased anonymous ubiquitinated protein levels in MG132-treated HPF cells. In conclusion, MAPK inhibitors differently affected the growth inhibition and death of MG132-treated HPF cells. Especially, p38 inhibitor attenuated HPF cell death by MG132, which was in part related to changes in ROS and GSH levels.

Involvement of p38 mitogen-activated protein kinase in the cell growth inhibition by sodium arsenite

2002 ◽  
Vol 190 (1) ◽  
pp. 29-37 ◽  
Author(s):  
Ja-Young Kim ◽  
Jung-A Choi ◽  
Tae-Hwan Kim ◽  
Young-Do Yoo ◽  
Jong-Il Kim ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cell Growth ◽  
Growth Inhibition ◽  
Sodium Arsenite ◽  
Mitogen Activated Protein Kinase ◽  
Cell Growth Inhibition ◽  
Mitogen Activated Protein

scholarly journals RARα2 expression is associated with disease progression and plays a crucial role in efficacy of ATRA treatment in myeloma

Blood ◽  
2009 ◽  
Vol 114 (3) ◽  
pp. 600-607 ◽  
Author(s):  
Siqing Wang ◽  
Guido Tricot ◽  
Lei Shi ◽  
Wei Xiong ◽  
Zhaoyang Zeng ◽  
...  
Keyword(s):  
Cell Death ◽  
Retinoic Acid ◽  
Growth Inhibition ◽  
Severe Combined Immunodeficiency ◽  
Gene Array ◽  
Genetic Alterations ◽  
Mitogen Activated Protein Kinase ◽  
Atra Treatment ◽  
All Trans Retinoic Acid ◽  
Mitogen Activated Protein

Abstract Specific genetic alterations in multiple myeloma (MM) may cause more aggressive diseases. Paired gene array analysis on 51 samples showed that retinoic acid (RA) receptor α (RARα) expression significantly increased at relapse compared with diagnosis. RARα encodes 2 major isoforms: RARα1 and RARα2. In this study, we examined the function of RARα2 in MM. Reverse transcription–polymerase chain reaction (RT-PCR) revealed ubiquitous RARα1 expression in MM cells, but RARα2 was expressed in 26 (32%) of 80 newly diagnosed patients and 10 (28%) of 36 MM cell lines. Patients with RARα2 expression had a significantly shorter overall survival on identical treatments. The presence of RARα2 remained significant on multivariate analysis. Knockdown of RARα2 but not RARα1 induced significant MM cell death and growth inhibition, and overexpressing RARα2 activated STAT3 and mitogen-activated protein kinase kinase (MEK)/extracellular signal–regulated kinase (ERK) signaling pathways. Interestingly, all-trans retinoic acid (ATRA) treatment induced potent cell death and growth inhibition in RARα2+ but not RARα2− MM cells; overexpressing RARα2 in RARα2-deficient MM cells restored sensitivity to ATRA. Furthermore, ATRA treatment significantly inhibited the growth of RARα2-overexpressing MM tumors in severe combined immunodeficiency (SCID) mouse model. These findings provide a rationale for RA-based therapy in aggressive RARα2+ MM.

scholarly journals Antitumor Activity of Phosphoinositide 3-Kinases Inhibitor, Copanlisib in Multiple Myeloma Cells

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5755-5755
Author(s):  
Yuko Tanaka ◽  
Seiichi Okabe ◽  
Tetsuzo Tauchi ◽  
Yoshikazu Ito ◽  
Kazuma Ohyashiki
Keyword(s):  
Cell Growth ◽  
Growth Inhibition ◽  
Signaling Pathway ◽  
Proteasome Inhibitor ◽  
Proteasome Inhibitors ◽  
Pi3k Signaling ◽  
Dependent Manner ◽  
Cell Growth Inhibition ◽  
Pi3k Signaling Pathway ◽  
Dose Dependent

Abstract Multiple myeloma (MM) is one of the common hematological malignancies and is a uniformly fatal disorder of B cells characterized by accumulation of abnormal plasma cells in the bone marrow. Proteasome inhibitor, bortezomib, and immunomodulatory drugs such as thalidomide and lenalidomide play important roles in the treatment of MM patients. Although novel agents including, e.g. bortezomib, have significantly improved the response and survival of patients with MM, a large number of patients eventually have relapsed. For the patients who relapse after treatment with novel agents, the prognosis is still poor. Thus circumstanced, alternative strategies are required for continued disease control. Phosphoinositide 3-kinases (PI3Ks) are a family of proteins involved in the regulator of cell growth, metabolism and proliferation. PI3K signaling pathway also plays a critical regulatory role in MM pathology, including survival, cellular proliferation, migration and angiogenesis. Therefore, PI3K signaling pathway may present attractive targets for MM treatment. Copanlisib also known as BAY80-6946 is a potent and highly selective reversible PI3K inhibitor. Copnalisib is currently investigated in a pivotal phase 2 clinical trial against hematological malignancy such as malignant lymphoma. We hypothesized that treatment with PI3K inhibitor and proteasome inhibitors together would result in enhanced therapeutic activity in MM cells. In this study, we investigated the efficacy of copanlisib by using the MM cell lines, RPMI8226, MM1.S and MM1.R and primary sample. 72 h treatment of copanlisib exhibits cell growth inhibition of MM cell lines in a dose dependent manner. The treatment of proteasome inhibitors, bortezomib and carfilzomib exhibits cell growth inhibition partially against RPMI8226 cells in the presence of feeder cell line, HS-5. We examined the intracellular signaling in the presence of HS-5. Phosphorylation of Akt and activation of caspase 3 and poly (ADP-ribose) polymerase (PARP) was partially reduced by carfilzomib or bortezomib in the presence of HS-5. We found that the treatment of copanlisib abrogated the protective effects of HS-5 in RPMI8226 cells. We examined the intracellular signaling after treatment of copanlisib. Activity of caspase 3 and poly (ADP-ribose) polymerase (PARP) was increased after copnlisib treatment in a dose dependent manner. Because PI3K signaling pathway regulates MM cell migration, we next evaluated the chemotactic response of MM cells to stromal cell-derived factor 1α (SDF-1α). We found that 4 h treatment of SDF-1α significantly induced the migration of MM cells compared to control medium. Treatment of copanlisib inhibited SDF-1α-stimulated chemotaxis in a dose dependent manner. We found that phosphorylation of Akt was reduced after copanlisib treatment suggesting that intracellular PI3K signaling pathway may play the important role in SDF-1α induced chemotaxis of MM cells. We investigated the copanlisib activity against MM cells. Combined treatment of MM cells with proteasome inhibitor, carfilzomib or bortezomib, and copanlisib caused significantly more cytotoxicity than each drugs alone. Phosphorylation of Akt was reduced and cleaved PARP was increased after copanlisib with or without proteasome inhibitor. We also found that copanlisib which was combinaed with carfilzomib or borteomib exhibited cell growth inhibition against MM primary sample. Data from this study suggested that administration of the PI3K inhibitor, copanlisib may be a powerful strategy against stroma-associated drug resistance of MM cells and enhance cytotoxic effects of proteasome inhibitors in those residual MM cells. Disclosures No relevant conflicts of interest to declare.

scholarly journals Chloroquine synergizes with FTS to enhance cell growth inhibition and cell death

Oncotarget ◽  
2013 ◽  
Vol 5 (1) ◽  
pp. 173-184 ◽  
Author(s):  
Eran Schmukler ◽  
Eya Wolfson ◽  
Roni Haklai ◽  
Galit Elad-Sfadia ◽  
Yoel Kloog ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Growth ◽  
Growth Inhibition ◽  
Cell Growth Inhibition ◽  
Enhance Cell Growth

scholarly journals Sulforaphane potentiates oxaliplatin-induced cell growth inhibition in colorectal cancer cells via induction of different modes of cell death

2010 ◽  
Vol 67 (5) ◽  
pp. 1167-1178 ◽  
Author(s):  
Bettina M. Kaminski ◽  
Andreas Weigert ◽  
Bernhard Brüne ◽  
Marco Schumacher ◽  
Uwe Wenzel ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Death ◽  
Cell Growth ◽  
Growth Inhibition ◽  
Cancer Cells ◽  
Cell Growth Inhibition ◽  
Colorectal Cancer Cells

scholarly journals Disrupting the Oncogenic Synergism between Nucleolin and Ras Results in Cell Growth Inhibition and Cell Death

PLoS ONE ◽  
2013 ◽  
Vol 8 (9) ◽  
pp. e75269 ◽  
Author(s):  
Sari Schokoroy ◽  
Dolly Juster ◽  
Yoel Kloog ◽  
Ronit Pinkas-Kramarski
Keyword(s):  
Cell Death ◽  
Cell Growth ◽  
Growth Inhibition ◽  
Cell Growth Inhibition

scholarly journals MnTE-2-PyP Suppresses Prostate Cancer Cell Growth via H2O2 Production

Antioxidants ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 490
Author(s):  
Yuxiang Zhu ◽  
Elizabeth A. Kosmacek ◽  
Arpita Chatterjee ◽  
Rebecca E. Oberley-Deegan
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Death ◽  
Cell Growth ◽  
Growth Inhibition ◽  
Cell Cycle Progression ◽  
Cell Growth Inhibition ◽  
Lncap Cells ◽  
Cycle Progression ◽  
Pc3 Cells

Prostate cancer patients are often treated with radiotherapy. MnTE-2-PyP, a superoxide dismutase (SOD) mimic, is a known radioprotector of normal tissues. Our recent work demonstrated that MnTE-2-PyP also inhibits prostate cancer progression with radiotherapy; however, the mechanisms remain unclear. In this study, we identified that MnTE-2-PyP-induced intracellular H2O2 levels are critical in inhibiting the growth of PC3 and LNCaP cells, but the increased H2O2 levels affected the two cancer cells differently. In PC3 cells, many proteins were thiol oxidized with MnTE-2-PyP treatment, including Ser/Thr protein phosphatase 1 beta catalytic subunit (PP1CB). This resulted in reduced PP1CB activity; however, overall cell cycle progression was not altered, so this is not the main mechanism of PC3 cell growth inhibition. High H2O2 levels by MnTE-2-PyP treatment induced nuclear fragmentation, which could be synergistically enhanced with radiotherapy. In LNCaP cells, thiol oxidation by MnTE-2-PyP treatment was not observed previously and, similarly to PC3 cells, there was no effect of MnTE-2-PyP treatment on cell cycle progression. However, in LNCaP cells, MnTE-2-PyP caused an increase in low RNA population and sub-G1 population of cells, which indicates that MnTE-2-PyP treatment may cause cellular quiescence or direct cancer cell death. The protein oxidative modifications and mitotic catastrophes caused by MnTE-2-PyP may be the major contributors to cell growth inhibition in PC3 cells, while in LNCaP cells, tumor cell quiescence or cell death appears to be major factors in MnTE-2-PyP-induced growth inhibition.

scholarly journals PSF Knockdown Enhances Apoptosis via Downregulation of LC3B in Human Colon Cancer Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Tamotsu Tsukahara ◽  
Yoshikazu Matsuda ◽  
Hisao Haniu
Keyword(s):  
Colon Cancer ◽  
Cell Death ◽  
Cell Growth ◽  
Growth Inhibition ◽  
Cancer Cells ◽  
Apoptotic Cell ◽  
Physiological Role ◽  
Colon Cancer Cells ◽  
Cell Growth Inhibition ◽  
Ht 29

Our previous study demonstrated that PTB-associated splicing factor (PSF) is an important regulator of cell death and plays critical roles in the survival and growth of colon cancer cells. However, the molecular mechanism that activates these downstream signaling events remains unknown. To address this issue, we investigated the effects of PSF knockdown in two different colon cancer cell lines, DLD-1 and HT-29. We found that knockdown of PSF markedly decreased the autophagic molecule LC3B in DLD-1 cells but not in HT-29 cells. Furthermore, DLD-1 cells were more susceptible to PSF knockdown-induced cell growth inhibition and apoptosis than HT-29 cells. This susceptibility is probably a result of LC3B inhibition, given the known relationship between autophagy and apoptosis. C3B is associated with a number of physiological processes, including cell growth and apoptotic cell death. Our results suggest that autophagy is inhibited by PSF knockdown and that apoptosis and cell growth inhibition may act together to mediate the PSF-LC3B signaling pathway. Furthermore, we found that the peroxisome proliferator-activated receptor gamma (PPARγ)-PSF complex induced LC3B downregulation in DLD-1 cells. The results of this study identify a new physiological role for the PSF-LC3B axis as a potential endogenous modulator of colon cancer treatment.

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