Tumor suppressor protein kinase Chk2 is a mediator of anoikis of intestinal epithelial cells

Berezkin, Alexander; Wang, Yanfei; Zagryazhskaya, Anna; Rosen, Kirill V.

doi:10.1002/ijc.26368

Cited by 14 publications

(15 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Anoikis resistance is one of the acquired capabilities of tumorigenic cells to disseminate. Increased oncogene and decreased tumor suppressor genes expression can improve protection from anoikis [61], [62]. In this study, melan-a melanocyte lineage submitted to anchorage blockade presented Ras activation in the first 30 minutes ( Figure 2A ) and some authors have demonstrated that Ras signaling can affect gene expression through DNA methylation.…”

Section: Discussionmentioning

confidence: 52%

Ras and Rac1, Frequently Mutated in Melanomas, Are Activated by Superoxide Anion, Modulate Dnmt1 Level and Are Causally Related to Melanocyte Malignant Transformation

et al. 2013

View full text Add to dashboard Cite

A melanocyte malignant transformation model was developed in our laboratory, in which different melanoma cell lines were obtained after submitting the non-tumorigenic melanocyte lineage melan-a to sequential cycles of anchorage impediment. Our group has already showed that increased superoxide level leads to global DNA hypermemethylation as well increased Dnmt1 expression few hours after melanocyte anchorage blockade. Here, we showed that Ras/Rac1/ERK signaling pathway is activated in melanocytes submitted to anchorage impediment, regulating superoxide levels, global DNA methylation, and Dnmt1 expression. Interestingly, Ras and Rac1 activation is not related to codon mutations, but instead regulated by superoxide. Moreover, the malignant transformation was drastically compromised when melan-a melanocytes were submitted to sequential cycles of anchorage blockage in the presence of a superoxide scavenger. This aberrant signaling pathway associated with a sustained stressful condition, which might be similar to conditions such as UV radiation and inflammation, seems to be an early step in malignant transformation and to contribute to an epigenetic reprogramming and the melanoma development.

show abstract

Section: Discussionmentioning

confidence: 52%

Ras and Rac1, Frequently Mutated in Melanomas, Are Activated by Superoxide Anion, Modulate Dnmt1 Level and Are Causally Related to Melanocyte Malignant Transformation

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Our study, for the first time, identified CHK2 as a novel mediator of anoikis in PTC cells, as has already been reported in intestinal epithelial cells [48]. Anoikis resistance is a hallmark of malignant cells and is believed to play a role in the survival of circulating tumor cells.…”

Section: Discussionmentioning

confidence: 49%

CHK2 Promotes Anoikis and is Associated with the Progression of Papillary Thyroid Cancer

Zhao

Chen

Hou

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Cell cycle checkpoint kinase 2 (CHK2) performs essential cellular functions and might be associated with tumorigenesis and tumor progression. Here, we explored the function and molecular mechanisms of CHK2 in the progression of papillary thyroid cancer (PTC). Methods: The expression levels of both total CHK2 and activated CHK2 (p-CHK2) in tissues from 100 PTC patients were detected and evaluated using immunohistochemistry. The roles of CHK2 on cell proliferation, invasion, migration, apoptosis and cancer stem cell (CSC) markers were investigated by CCK-8, Transwell, flow cytometry, western blot and ALDEFLOUR assay. PTC cells cultured in suspension conditions were assayed for anoikis. The anchorage-independent condition was further detected by soft agar colony formation assay. Furthermore, anoikis associated regulatory proteins were explored by western blot and verified by forced downregulation experiment, respectively. Results: We found that the levels of both CHK2 and p-CHK2 were significantly upregulated in PTC cancer tissues compared with those in tumor-adjacent tissues. The overexpression of p-CHK2 in primary tumor tissues was associated with tumor aggressiveness and metastatic potential. However, the levels of both CHK2 and p-CHK2 were decreased in metastatic lymph nodes. Our results showed that CHK2 upregulated the levels of CSC markers with no effect on cell proliferation, invasion and migration. Interestingly, we revealed a previously undescribed anoikis-promoting role for CHK2 in PTC. Specifically, the detachment of PTC cells from the extracellular matrix (ECM) triggers CHK2 degradation. Then, the forced downregulation of CHK2 rescued PTC cells from anoikis, but no effect was observed on the apoptosis of adherent PTC cells. Additionally, as a novel regulator of anoikis, CHK2 can induce cell death in a p53-independent manner via the regulation of PRAS40 activation. Conclusion: High expression levels of CHK2 and p-CHK2 were associated with the progression of PTC. Our results defined an unexpected role for CHK2 as a mediator of anoikis that functions through the regulation of PRAS40 activation, which may be associated with the survival of circulating tumor cells and metastatic behavior.

show abstract

“…We found previously that anoikis of intestinal epithelial cells is driven by multiple mechanisms mediated by detachment-induced changes in the expression of various regulators of apoptosis. 4,18,24,25 Importantly for this study, we and others observed previously that a small fraction of nonmalignant intestinal epithelial cells, such as IEC-18 and Hkh-2 used in this study, remains viable after being cultured without adhesion to the ECM and if expanded displays pronounced and well reproducible resistance to anoikis 22,23 (the nature of this cellular heterogeneity is presently not known). These data indicate that intestinal epithelial cells contain a cell population in which at least some of the anoikis-promoting mechanisms are blocked.…”

Section: Discussionmentioning

confidence: 70%

“…4,24,25 We also established that oncogenic RAS, an oncoprotein that often occurs in colorectal cancer, blocks anoikis of colon cancer cells via multiple mechanisms that involve the downregulation of pro-apoptotic proteins BAK1/Bak and CASP2/caspase-2 and the upregulation of BCL2L1 as well as that of apoptosis inhibitors BIRC3/cIAP2 and XIAP. 4,5,18,26 In searching for the mechanisms by which detachment of nonmalignant intestinal epithelial cells blocks their growth we found that growth arrest of detached cells is driven by their detachment-induced autophagy.…”

Section: Introductionmentioning

confidence: 94%

See 1 more Smart Citation

Upregulation of ATG3 contributes to autophagy induced by the detachment of intestinal epithelial cells from the extracellular matrix, but promotes autophagy-independent apoptosis of the attached cells

Zagryazhskaya

Li²,

Koomson

et al. 2015

Autophagy

Self Cite

View full text Add to dashboard Cite

(2015) Upregulation of ATG3 contributes to autophagy induced by the detachment of intestinal epithelial cells from the extracellular matrix, but promotes autophagy-independent apoptosis of the attached cells, Autophagy, 11:8, 1230-1246, DOI: 10.1080/15548627.2015 Keywords: autophagy, apoptosis, anoikis, ATG3, ATG7, extracellular matrixAbbreviations: ATG, autophagy-related; BCL2L1, Bcl2-like1; CDK4, cyclin-dependent kinase 4; ECM, extracellular matrix; EGFR, epidermal growth factor receptor; GABARAP, GABA(A) receptor-associated protein; GFP, green fluorescent protein; LC3/ MAP1LC3, microtubule-associated protein 1 light chain 3; PE, phosphatidylethanolamine; qPCR, quantitative polymerase chain reaction; SD, standard deviation; SH3GLB1/Bif1, SH3-domain GRB2-like endophilin B1; siRNA, small interfering RNA; UVRAG, UV radiation resistance-associated.Detachment of nonmalignant intestinal epithelial cells from the extracellular matrix (ECM) triggers their growth arrest and, ultimately, apoptosis. In contrast, colorectal cancer cells can grow without attachment to the ECM. This ability is critical for their malignant potential. We found previously that detachment-induced growth arrest of nonmalignant intestinal epithelial cells is driven by their detachment-triggered autophagy, and that RAS, a major oncogene, promotes growth of detached cells by blocking such autophagy. In an effort to identify the mechanisms of detachment-induced autophagy and growth arrest of nonmalignant cells we found here that detachment of these cells causes upregulation of ATG3 and that ATG3 upregulation contributes to autophagy and growth arrest of detached cells. We also observed that when ATG3 expression is artificially increased in the attached cells, ATG3 promotes neither autophagy nor growth arrest but triggers their apoptosis. ATG3 upregulation likely promotes autophagy of the detached but not that of the attached cells because detachment-dependent autophagy requires other detachmentinduced events, such as the upregulation of ATG7. We further observed that those few adherent cells that do not die by apoptosis induced by ATG3 become resistant to apoptosis caused by cell detachment, a property that is critical for the ability of normal epithelial cells to become malignant. We conclude that cell-ECM adhesion can switch ATG3 functions: when upregulated in detached cells in the context of other autophagy-promoting events, ATG3 contributes to autophagy. However, when overexpressed in the adherent cells, in the circumstances not favoring autophagy, ATG3 triggers apoptosis.

show abstract

Tumor suppressor protein kinase Chk2 is a mediator of anoikis of intestinal epithelial cells

Cited by 14 publications

References 30 publications

Ras and Rac1, Frequently Mutated in Melanomas, Are Activated by Superoxide Anion, Modulate Dnmt1 Level and Are Causally Related to Melanocyte Malignant Transformation

Ras and Rac1, Frequently Mutated in Melanomas, Are Activated by Superoxide Anion, Modulate Dnmt1 Level and Are Causally Related to Melanocyte Malignant Transformation

CHK2 Promotes Anoikis and is Associated with the Progression of Papillary Thyroid Cancer

Upregulation of ATG3 contributes to autophagy induced by the detachment of intestinal epithelial cells from the extracellular matrix, but promotes autophagy-independent apoptosis of the attached cells

Contact Info

Product

Resources

About