Down Regulation of C-MYC and MAX Genes Is Associated to Inhibition of Protein Phosphatase 2A in K562 Human Leukemia Cells

1995 ◽  
Vol 215 (3) ◽  
pp. 889-895 ◽  
Author(s):  
A. Lerga ◽  
B. Belandia ◽  
M.D. Delgado ◽  
M.A. Cuadrado ◽  
C. Richard ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
Down Regulation ◽  
Human Leukemia Cells ◽  
Phosphatase 2A

Arsenic Trioxide Induces Erythroid Differentiation and Apoptosis of K562 Human Leukemia Cells through the Down-Regulation of Bcl-2

2005 ◽  
Vol 40 (2) ◽  
pp. 93
Author(s):  
Yong-Kyu You ◽  
Hee-Jeong Cheong ◽  
Jong-Ho Won ◽  
Sook-Ja Kim ◽  
Sang-Byung Bae ◽  
...  
Keyword(s):  
Arsenic Trioxide ◽  
Erythroid Differentiation ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
Down Regulation ◽  
Human Leukemia Cells

scholarly journals Apoptosis Induced by the Kinase Inhibitor BAY 43-9006 in Human Leukemia Cells Involves Down-regulation of Mcl-1 through Inhibition of Translation

2005 ◽  
Vol 280 (42) ◽  
pp. 35217-35227 ◽  
Author(s):  
Mohamed Rahmani ◽  
Eric Maynard Davis ◽  
Cheryl Bauer ◽  
Paul Dent ◽  
Steven Grant
Keyword(s):  
Kinase Inhibitor ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
Down Regulation ◽  
Human Leukemia Cells

scholarly journals Naja atra Cardiotoxin 3 Elicits Autophagy and Apoptosis in U937 Human Leukemia Cells through the Ca2+/PP2A/AMPK Axis

Toxins ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 527 ◽  
Author(s):  
Jing-Ting Chiou ◽  
Yi-Jun Shi ◽  
Liang-Jun Wang ◽  
Chia-Hui Huang ◽  
Yuan-Chin Lee ◽  
...  
Keyword(s):  
Cell Death ◽  
Membrane Damage ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
U937 Cells ◽  
Cell Membrane Damage ◽  
Human Leukemia Cells ◽  
Phosphatase 2A ◽  
Induced Apoptosis ◽  
Naja Atra

Cardiotoxins (CTXs) are suggested to exert their cytotoxicity through cell membrane damage. Other studies show that penetration of CTXs into cells elicits mitochondrial fragmentation or lysosome disruption, leading to cell death. Considering the role of AMPK-activated protein kinase (AMPK) in mitochondrial biogenesis and lysosomal biogenesis, we aimed to investigate whether the AMPK-mediated pathway modulated Naja atra (Taiwan cobra) CTX3 cytotoxicity in U937 human leukemia cells. Our results showed that CTX3 induced autophagy and apoptosis in U937 cells, whereas autophagic inhibitors suppressed CTX3-induced apoptosis. CTX3 treatment elicited Ca2+-dependent degradation of the protein phosphatase 2A (PP2A) catalytic subunit (PP2Acα) and phosphorylation of AMPKα. Overexpression of PP2Acα mitigated the CTX3-induced AMPKα phosphorylation. CTX3-induced autophagy was via AMPK-mediated suppression of the Akt/mTOR pathway. Removal of Ca2+ or suppression of AMPKα phosphorylation inhibited the CTX3-induced cell death. CTX3 was unable to induce autophagy and apoptosis in U937 cells expressing constitutively active Akt. Met-modified CTX3 retained its membrane-perturbing activity, however, it did not induce AMPK activation and death of U937 cells. These results conclusively indicate that CTX3 induces autophagy and apoptosis in U937 cells via the Ca2+/PP2A/AMPK axis, and suggest that the membrane-perturbing activity of CTX3 is not crucial for the cell death signaling pathway induction.

Highly Synergistic Interaction between Farnesyltransferase Inhibitors and the Chk1 Inhibitor UCN-01 to Induce Apoptosis in Human Leukemia Cells through Interruption of Both Akt and MEK/ERK Pathways and Activation of SEK1/JNK.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3403-3403
Author(s):  
Yun Dai ◽  
Mohamed Rahmani ◽  
Xin-Yan Pei ◽  
Payal Khanna ◽  
Paul Dent ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Combined Treatment ◽  
Ectopic Expression ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
Farnesyltransferase Inhibitors ◽  
Down Regulation ◽  
Human Leukemia Cells ◽  
Chk1 Inhibitor ◽  
Constitutively Active

Abstract Ras mutations, which result in constitutive Ras activation, occur frequently in human malignancies, including leukemia. This finding has prompted the development of farnesyltransferase inhibitors (FTIs), which interfere with Ras farnesylation and membrane translocation necessary for Ras function. However, FTIs alone have not yet fulfilled their clinical potential, raising the possibility that their role may lie in combination with other agents. The present studies examined interactions between the farnesyltransferase inhibitor L744832 and the Chk1 inhibitor UCN-01 in human leukemia cells. Combined exposure of U937 cells to sub-toxic concentrations of UCN-01 (100nM) and the FTI L744352 (10μM) resulted in a dramatic and highly synergistic increase in mitochondrial dysfunction, apoptosis, and loss of clonogenicity. Similar interactions were noted in other leukemia cells (HL-60, Raji, Jurkat) and primary AML blasts, and with other farnesyltransferase inhibitors (e.g., FTI-277). These events were accompanied by cleavage of the anti-apoptotic proteins Bcl-2, XIAP, and Mcl-1. Co-administration of L744832 blocked UCN-01-mediated phosphorylation of MEK/ERK, leading to down-regulation of phospho-CREB and -p90RSK, and activation of p34cdc2 and SEK/JNK. Combined treatment also resulted in pronounced reductions in levels of phospho-Akt, -GSK, -p70S6K, -mTOR, -FKHR, -caspase-9, and -Bad. Ectopic expression of Bcl-2 or Bcl-xL but not dominant-negative caspase-8 blocked UCN-01/L744832-mediated mitochondrial dysfunction and apoptosis, but did not prevent activation of p34cdc2 and JNK, or inactivation of MEK/ERK and Akt. Enforced expression of myristolated Akt but not constitutively-active MEK significantly attenuated UCN-01/L744832-induced apoptosis. However, dual transfection with constitutively active Akt and MEK resulted in further protection from UCN-01/L744832-mediated lethality. Finally, down-regulation of JNK1 by siRNA significantly reduced the lethality of the UCN-01/L744832 regimen. Together, these findings suggest that farnesyltransferase inhibitors interrupt the cytoprotective Akt and MAPK pathways while reciprocally activating SAPK/JNK in leukemia cells exposed to UCN-01, and in so doing, dramatically increase mitochondria-dependent apoptosis. They also raise the possibility that combined treatment with FTIs and UCN-01 may represent a novel therapeutic strategy in leukemia.

scholarly journals Cancerous inhibitor of protein phosphatase 2A determines bortezomib-induced apoptosis in leukemia cells

Haematologica ◽  
2012 ◽  
Vol 98 (5) ◽  
pp. 729-738 ◽  
Author(s):  
C.-Y. Liu ◽  
C.-W. Shiau ◽  
H.-Y. Kuo ◽  
H.-P. Huang ◽  
M.-H. Chen ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Leukemia Cells ◽  
Phosphatase 2A ◽  
Induced Apoptosis
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