scholarly journals Involvement of general control nonderepressible kinase 2 in cancer cell apoptosis by posttranslational mechanisms

2015 ◽  
Vol 26 (6) ◽  
pp. 1044-1057 ◽  
Author(s):  
Chen Wei ◽  
Ma Lin ◽  
Bian Jinjun ◽  
Feng Su ◽  
Cao Dan ◽  
...  

General control nonderepressible kinase 2 (GCN2) is a promising target for cancer therapy. However, the role of GCN2 in cancer cell survival or death is elusive; further, small molecules targeting GCN2 signaling are not available. By using a GCN2 level-based drug screening assay, we found that GCN2 protein level critically determined the sensitivity of the cancer cells toward Na+,K+-ATPase ligand–induced apoptosis both in vitro and in vivo, and this effect was largely dependent on C/EBP homologous protein (CHOP) induction. Further analysis revealed that GCN2 is a short-lived protein. In A549 lung carcinoma cells, cellular β-arrestin1/2 associated with GCN2 and maintained the GCN2 protein level at a low level by recruiting the E3 ligase NEDD4L and facilitating consequent proteasomal degradation. However, Na+,K+-ATPase ligand treatment triggered the phosphorylation of GCN2 at threonine 899, which increased the GCN2 protein level by disrupting the formation of GCN2–β-arrestin–NEDD4L ternary complex. The enhanced GCN2 level, in turn, aggravated Na+,K+-ATPase ligand–induced cancer cell apoptosis. Our findings reveal that GCN2 can exert its proapoptotic function in cancer cell death by posttranslational mechanisms. Moreover, Na+,K+-ATPase ligands emerge as the first identified small-molecule drugs that can trigger cancer cell death by modulating GCN2 signaling.

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yu Wang ◽  
Liming Zhu ◽  
Mei Guo ◽  
Gang Sun ◽  
Kun Zhou ◽  
...  

AbstractWHSC1 is a histone methyltransferase that facilitates histone H3 lysine 36 dimethylation (H3K36me2), which is a permissive mark associated with active transcription. In this study, we revealed how WHSC1 regulates tumorigenesis and chemosensitivity of colorectal cancer (CRC). Our data showed that WHSC1 as well as H3K36me2 were highly expressed in clinical CRC samples, and high WHSC1 expression is associated with poorer prognosis in CRC patients. WHSC1 reduction promoted colon cancer cell apoptosis both in vivo and in vitro. We found that B cell lymphoma-2 (BCL2) expression, an anti-apoptotic protein, is markedly decreased in after WHSC1 depletion. Mechanistic characterization indicated that WHSC1 directly binds to the promoter region of BCL2 gene and regulate its H3K36 dimethylation level. What’s more, our study indicated that WHSC1 depletion promotes chemosensitivity in CRC cells. Together, our results suggested that WHSC1 and H3K36me2 modification might be optimal therapeutic targets to disrupt CRC progression and WHSC1-targeted therapy might potentially overcome the resistance of chemotherapeutic agents.


2015 ◽  
Vol 3 (48) ◽  
pp. 9383-9396 ◽  
Author(s):  
Xin Liang ◽  
Ying Yang ◽  
Lijun Wang ◽  
Xianbing Zhu ◽  
Xiaowei Zeng ◽  
...  

Rapamycin–NaHCO3-loaded HMs combined CQ–NaHCO3-loaded HMs could efficiently induce cancer cell death through apoptosis with autophagosome both in vitro and in vivo.


2018 ◽  
Vol 9 ◽  
Author(s):  
Vanessa Kaplum ◽  
Anelise C. Ramos ◽  
Marcia E. L. Consolaro ◽  
Maria A. Fernandez ◽  
Tânia Ueda-Nakamura ◽  
...  

2012 ◽  
Vol 29 (2) ◽  
pp. 515-522 ◽  
Author(s):  
HONG LUAN MAO ◽  
YINGXIN PANG ◽  
XIAOLEI ZHANG ◽  
FANG YANG ◽  
JINGFANG ZHENG ◽  
...  

2013 ◽  
Vol 130 (1) ◽  
pp. e130
Author(s):  
C. Rivard Hunt ◽  
M. Geller ◽  
C. Evans ◽  
R. Vogel ◽  
S. Ramakrishnan ◽  
...  

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