Effect of the actin- and calcium-regulating activities of ITPKB on the metastatic potential of lung cancer cells

2018 ◽  
Vol 475 (12) ◽  
pp. 2057-2071 ◽  
Author(s):  
Selina Bäder ◽  
Elina Glaubke ◽  
Saskia Grüb ◽  
Stefanie Muhs ◽  
Jasmin Wellbrock ◽  
...  

Inositol-1,4,5-trisphosphate 3-kinase-A (ITPKA) exhibits oncogenic activity in lung cancer cells by regulating Ins(1,4,5)P3-mediated calcium release and cytoskeletal dynamics. Since, in normal cells, ITPKA is mainly expressed in the brain, it is an excellent target for selected therapy of lung cancer. However, ITPKB is strongly expressed in normal lung tissues, but is down-regulated in lung cancer cells by miR-375, assuming that ITPKB might have tumor suppressor activity. In addition, ITPKB binds to F-actin making it likely that, similar to ITPKA, it controls actin dynamics. Thus, the treatment of ITPKA-expressing lung cancer with ITPKA inhibitors simultaneously inhibiting ITPKB may counteract the therapy. Based on these considerations, we analyzed if ITPKB controls actin dynamics and if the protein reduces aggressive progression of lung cancer cells. We found that ITPKB bundled F-actin in cell-free systems. However, the stable expression of ITPKB in H1299 lung cancer cells, exhibiting very low endogenous ITPKB expression, had no significant effect on the actin structure. In addition, our data show that ITPKB negatively controls transmigration of H1299 cells in vitro by blocking Ins(1,4,5)P3-mediated calcium release. On the other hand, colony formation was stimulated by ITPKB, independent of Ins(1,4,5)P3-mediated calcium signals. However, dissemination of H1299 cells from the skin to the lung in NOD scid gamma mice was not significantly affected by ITPKB expression. In summary, ITPKB does not affect the cellular actin structure and does not suppress dissemination of human lung cancer cells in mice. Thus, our initial hypotheses that ITPKB exhibits tumor suppressor activity could not be supported.

2020 ◽  
Vol 39 (11) ◽  
pp. 2077-2084
Author(s):  
Priyadarshini Ravichandran ◽  
Simon A. Davis ◽  
Himali Vashishtha ◽  
Azad L. Gucwa ◽  
Daniel S. Ginsburg

Oncogene ◽  
2005 ◽  
Vol 24 (56) ◽  
pp. 8229-8239 ◽  
Author(s):  
Xiaolin Bi ◽  
Tamara Jones ◽  
Fatima Abbasi ◽  
Heuijung Lee ◽  
Brian Stultz ◽  
...  

2013 ◽  
Vol 13 (1) ◽  
pp. 90 ◽  
Author(s):  
Yong-Ju Li ◽  
Chun-Hong Wang ◽  
Ya Zhou ◽  
Zheng-Yuan Liao ◽  
Shun-Fei Zhu ◽  
...  

2020 ◽  
Vol 40 (10) ◽  
Author(s):  
Anfang Cui ◽  
Yuchan Xue ◽  
Xi’ao Wang ◽  
Yanhong Huang ◽  
Xiaolin Han ◽  
...  

Abstract Non–small cell lung cancer (NSCLC) is one of the most common causes of cancer-related mortality globally. However, the mechanism underlying NSCLC is not fully understood. Here, we investigated the role of cancer-related regulator of actin dynamics (CRAD) in NSCLC. We showed that CRAD was up-regulated in human NSCLC tissues and lung cancer cell lines. Lentivirus-mediated knockdown of CRAD repressed the proliferation and colony growth of A549 and H1299 cells. Apoptosis was enhanced by CRAD silencing in both cells, implicating that CRAD might maintain the survival of lung cancer cells. Microarray and bioinformatic assay revealed that CRAD directly or indirectly regulated diverse genes, including those involved in cell cycle and DNA damage repair. qRT-PCR and Western blot results confirmed the dysregulated genes as shown in microarray analysis. Claudin 4 was up-regulated in CRAD silenced A549 cells. The knockdown of Claudin 4 blocked the effects of CRAD on the expression of cell cycle and apoptosis effectors and enhanced the viability of A549 cells with CRAD down-regulation. Taken together, our findings demonstrate that CRAD acts as an oncogene in NSCLC at least partly through repressing Claudin 4.


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