Effect of the actin- and calcium-regulating activities of ITPKB on the metastatic potential of lung cancer cells
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Effect of the actin- and calcium-regulating activities of ITPKB on the metastatic potential of lung cancer cells. / Bäder, Selina; Glaubke, Elina; Grüb, Saskia; Muhs, Stefanie; Wellbrock, Jasmin; Nalaskowski, Marcus; Lange, Tobias; Windhorst, Sabine.
in: BIOCHEM J, Jahrgang 475, Nr. 12, 26.06.2018, S. 2057-2071.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Effect of the actin- and calcium-regulating activities of ITPKB on the metastatic potential of lung cancer cells
AU - Bäder, Selina
AU - Glaubke, Elina
AU - Grüb, Saskia
AU - Muhs, Stefanie
AU - Wellbrock, Jasmin
AU - Nalaskowski, Marcus
AU - Lange, Tobias
AU - Windhorst, Sabine
N1 - © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.
PY - 2018/6/26
Y1 - 2018/6/26
N2 - 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.
AB - 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.
KW - Journal Article
U2 - 10.1042/BCJ20180238
DO - 10.1042/BCJ20180238
M3 - SCORING: Journal article
C2 - 29871874
VL - 475
SP - 2057
EP - 2071
JO - BIOCHEM J
JF - BIOCHEM J
SN - 0264-6021
IS - 12
ER -