The ability of cells to switch between different invasive modes during metastasis, also known as invasion plasticity, is an important characteristic of tumor cells that makes them able to resist treatment targeted to a particular invasion mode. Due to the rapid changes in cell morphology during the transition between mesenchymal and amoeboid invasion, it is evident that this process requires remodeling of the cytoskeleton. Although the role of the actin cytoskeleton in cell invasion and plasticity is already quite well described, the contribution of microtubules is not yet fully clarified. It is not easy to infer whether destabilization of microtubules leads to higher invasiveness or the opposite since the complex microtubular network acts differently in diverse invasive modes. While mesenchymal migration typically requires microtubules at the leading edge of migrating cells to stabilize protrusions and form adhesive structures, amoeboid invasion is possible even in the absence of long, stable microtubules, albeit there are also cases of amoeboid cells where microtubules contribute to effective migration. Moreover, complex crosstalk of microtubules with other cytoskeletal networks participates in invasion regulation. Altogether, microtubules play an important role in tumor cell plasticity and can be therefore targeted to affect not only cell proliferation but also invasive properties of migrating cells.

• Klíčová slova
• 3D migration, amoeboid, cancer, invasion plasticity, mesenchymal, microtubules,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

P21-activated kinases (PAKs) are involved in the regulation of multiple processes including cell proliferation, adhesion and migration. However, the current knowledge about their function is mainly based on results obtained in adherent cell types. We investigated the effect of group I PAK inhibition using the compound IPA-3 in a variety of human leukemic cell lines (JURL-MK1, MOLM-7, K562, CML-T1, HL-60, Karpas-299, Jurkat, HEL) as well as in primary blood cells. IPA-3 induced cell death with EC50 ranging from 5 to more than 20 μM. Similar range was found for IPA-3-mediated dephosphorylation of a known PAK downstream effector, cofilin. The cell death was associated with caspase-3 activation, PARP cleavage and apoptotic DNA fragmentation. In parallel, 20 μM IPA-3 treatment induced rapid and marked decrease of the cell adhesivity to fibronectin. Per contra, partial reduction of PAK activity using lower dose IPA-3 or siRNA resulted in a slight increase in the cell adhesivity. The changes in the cell adhesivity were also studied using real-time microimpedance measurement and by interference reflection microscopy. Significant differences in the intracellular IPA-3 level among various cell lines were observed indicating that an active mechanism is involved in IPA-3 transport.

• MeSH
• apoptóza účinky léků   MeSH
• buněčná adheze účinky léků   MeSH
• disulfidy metabolismus   farmakologie   MeSH
• faktory depolymerizující aktin chemie   metabolismus   MeSH
• fibronektiny metabolismus   MeSH
• fosforylace účinky léků   MeSH
• hematopoéza účinky léků   MeSH
• inhibitory proteinkinas metabolismus   farmakologie   MeSH
• intracelulární prostor účinky léků   metabolismus   MeSH
• krevní buňky cytologie   účinky léků   MeSH
• leukemie patologie   MeSH
• lidé MeSH
• lymfom patologie   MeSH
• malá interferující RNA genetika   MeSH
• naftoly metabolismus   farmakologie   MeSH
• p21 aktivované kinasy antagonisté a inhibitory   nedostatek   genetika   MeSH
• proliferace buněk účinky léků   MeSH
• regulace genové exprese účinky léků   MeSH
• serin metabolismus   MeSH
• umlčování genů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• disulfidy MeSH
• faktory depolymerizující aktin MeSH
• fibronektiny MeSH
• inhibitory proteinkinas MeSH
• IPA-3 compound MeSH Prohlížeč
• malá interferující RNA MeSH
• naftoly MeSH
• p21 aktivované kinasy MeSH
• serin MeSH