scholarly journals Sensitization of multidrug-resistant human cancer cells to Hsp90 inhibitors by down-regulation of SIRT1

Oncotarget ◽  
2015 ◽  
Vol 6 (34) ◽  
pp. 36202-36218 ◽  
Author(s):  
Hak-Bong Kim ◽  
Su-Hoon Lee ◽  
Jee-Hyun Um ◽  
Won Keun Oh ◽  
Dong-Wan Kim ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Human Cancer ◽  
Multidrug Resistant ◽  
Hsp90 Inhibitors ◽  
Down Regulation ◽  
Human Cancer Cells

scholarly journals Down-regulation of the Tumor Suppressor C-terminal Src Kinase (Csk)-binding Protein (Cbp)/PAG1 Is Mediated by Epigenetic Histone Modifications via the Mitogen-activated Protein Kinase (MAPK)/Phosphatidylinositol 3-Kinase (PI3K) Pathway

2011 ◽  
Vol 286 (18) ◽  
pp. 15698-15706 ◽  
Author(s):  
Kei Suzuki ◽  
Chitose Oneyama ◽  
Hironobu Kimura ◽  
Shoji Tajima ◽  
Masato Okada
Keyword(s):  
Tumor Suppressor ◽  
Cancer Cells ◽  
Histone Modifications ◽  
Human Cancer ◽  
Methylation Status ◽  
Adaptor Protein ◽  
Pi3k Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Down Regulation ◽  
Human Cancer Cells

The transmembrane adaptor protein Cbp (or PAG1) functions as a suppressor of Src-mediated tumor progression by promoting the inactivation of Src. The expression of Cbp is down-regulated in Src-transformed cells and in various human cancer cells, suggesting a potential role for Cbp as a tumor suppressor. However, the mechanisms underlying the down-regulation of Cbp remain unknown. The present study shows that Cbp expression is down-regulated by epigenetic histone modifications via the MAPK/PI3K pathway. In mouse embryonic fibroblasts, transformation by oncogenic Src and Ras induced a marked down-regulation of Cbp expression. The levels of Cbp expression were inversely correlated with the activity of MEK and Akt, and Cbp down-regulation was suppressed by inhibiting MEK and PI3K. Src transformation did not affect the stability of Cbp mRNA, the transcriptional activity of the cbp promoter, or the DNA methylation status of the cbp promoter CpG islands. However, Cbp expression was restored by treatment with histone deacetylase (HDAC) inhibitors and by siRNA-mediated knockdown of HDAC1/2. Src transformation significantly decreased the acetylation levels of histone H4 and increased the trimethylation levels of histone H3 lysine 27 in the cbp promoter. EGF-induced Cbp down-regulation was also suppressed by inhibiting MEK and HDAC. Furthermore, the inhibition of MEK or HDAC restored Cbp expression in human cancer cells harboring Cbp down-regulation through promoter hypomethylation. These findings suggest that Cbp down-regulation is primarily mediated by epigenetic histone modifications via oncogenic MAPK/PI3K pathways in a subset of cancer cells.

p53-Independent Down-Regulation of Mdm2 in Human Cancer Cells Treated with Adriamycin

2000 ◽  
Vol 3 (2) ◽  
pp. 122-128 ◽  
Author(s):  
Yongxian Ma ◽  
Renqi Yuan ◽  
Qinghui Meng ◽  
Itzhak D. Goldberg ◽  
Eliot M. Rosen ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Human Cancer ◽  
Down Regulation ◽  
Human Cancer Cells

M-CSF gene transduction in multidrug-resistant human cancer cells to enhance anti-P-glycoprotein antibody-dependent macrophage-mediated cytotoxicity

1993 ◽  
Vol 54 (5) ◽  
pp. 851-857 ◽  
Author(s):  
Yuji Heike ◽  
Saburo Sone ◽  
Seiji Yano ◽  
Hiroyuki Seimiya ◽  
Takashi Tsuruo ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Human Cancer ◽  
Multidrug Resistant ◽  
Gene Transduction ◽  
Human Cancer Cells ◽  
P Glycoprotein

p53 Inhibits Adriamycin-Induced Down-Regulation of Cyclin D1 Expression in Human Cancer Cells

2002 ◽  
Vol 290 (3) ◽  
pp. 1101-1107 ◽  
Author(s):  
Jianghua Shao ◽  
Fuminori Teraishi ◽  
Koh Katsuda ◽  
Noriaki Tanaka ◽  
Toshiyoshi Fujiwara
Keyword(s):  
Cyclin D1 ◽  
Cancer Cells ◽  
Human Cancer ◽  
Down Regulation ◽  
Human Cancer Cells

scholarly journals Ectopic over-expression of tristetraprolin in human cancer cells promotes biogenesis of let-7 by down-regulation of Lin28

2011 ◽  
Vol 40 (9) ◽  
pp. 3856-3869 ◽  
Author(s):  
Chae Won Kim ◽  
Mai-Tram Vo ◽  
Hong Kyeung Kim ◽  
Hyun Hee Lee ◽  
Nal Ae Yoon ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Human Cancer ◽  
Down Regulation ◽  
Over Expression ◽  
Human Cancer Cells

scholarly journals Changes in phospholipase D isoform activity and expression in multidrug-resistant human cancer cells

2000 ◽  
Vol 85 (6) ◽  
pp. 882-888 ◽  
Author(s):  
Giusy Fiucci ◽  
Malgorzata Czarny ◽  
Yaakov Lavie ◽  
Di Zhao ◽  
Brygida Berse ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Phospholipase D ◽  
Human Cancer ◽  
Multidrug Resistant ◽  
Human Cancer Cells

Mechanisms involved in down-regulation of glutathione s-transferases alpha in human cancer cells

1995 ◽  
Vol 121 (S1) ◽  
pp. A18-A18
Author(s):  
W. A. Schultz ◽  
P. Eickelmann ◽  
A. Clairmont ◽  
T. Ebert ◽  
F. Morel ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Human Cancer ◽  
Down Regulation ◽  
Human Cancer Cells ◽  
Glutathione S Transferases

scholarly journals Targeting of KRAS mutant tumors by HSP90 inhibitors involves degradation of STK33

2012 ◽  
Vol 209 (4) ◽  
pp. 697-711 ◽  
Author(s):  
Ninel Azoitei ◽  
Christopher M. Hoffmann ◽  
Jana M. Ellegast ◽  
Claudia R. Ball ◽  
Kerstin Obermayer ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Human Cancer ◽  
Human Colon ◽  
Dependent Manner ◽  
Tumor Initiating Cells ◽  
Hsp90 Inhibitors ◽  
Hsp90 Inhibition ◽  
Human Cancer Cells

Previous efforts to develop drugs that directly inhibit the activity of mutant KRAS, the most commonly mutated human oncogene, have not been successful. Cancer cells driven by mutant KRAS require expression of the serine/threonine kinase STK33 for their viability and proliferation, identifying STK33 as a context-dependent therapeutic target. However, specific strategies for interfering with the critical functions of STK33 are not yet available. Here, using a mass spectrometry-based screen for STK33 protein interaction partners, we report that the HSP90/CDC37 chaperone complex binds to and stabilizes STK33 in human cancer cells. Pharmacologic inhibition of HSP90, using structurally divergent small molecules currently in clinical development, induced proteasome-mediated degradation of STK33 in human cancer cells of various tissue origin in vitro and in vivo, and triggered apoptosis preferentially in KRAS mutant cells in an STK33-dependent manner. Furthermore, HSP90 inhibitor treatment impaired sphere formation and viability of primary human colon tumor-initiating cells harboring mutant KRAS. These findings provide mechanistic insight into the activity of HSP90 inhibitors in KRAS mutant cancer cells, indicate that the enhanced requirement for STK33 can be exploited to target mutant KRAS-driven tumors, and identify STK33 depletion through HSP90 inhibition as a biomarker-guided therapeutic strategy with immediate translational potential.

Sign in / Sign up

Export Citation Format

Share Document