Mitotic Spindle Assembly and Genomic Stability in Breast Cancer Require PI3K-C2α Scaffolding Function.

Cancer cell (2017-10-11)
Federico Gulluni, Miriam Martini, Maria Chiara De Santis, Carlo Cosimo Campa, Alessandra Ghigo, Jean Piero Margaria, Elisa Ciraolo, Irene Franco, Ugo Ala, Laura Annaratone, Davide Disalvatore, Giovanni Bertalot, Giuseppe Viale, Anna Noatynska, Mara Compagno, Sara Sigismund, Filippo Montemurro, Marcus Thelen, Fan Fan, Patrick Meraldi, Caterina Marchiò, Salvatore Pece, Anna Sapino, Roberto Chiarle, Pier Paolo Di Fiore, Emilio Hirsch
RESUMEN

Proper organization of the mitotic spindle is key to genetic stability, but molecular components of inter-microtubule bridges that crosslink kinetochore fibers (K-fibers) are still largely unknown. Here we identify a kinase-independent function of class II phosphoinositide 3-OH kinase α (PI3K-C2α) acting as limiting scaffold protein organizing clathrin and TACC3 complex crosslinking K-fibers. Downregulation of PI3K-C2α causes spindle alterations, delayed anaphase onset, and aneuploidy, indicating that PI3K-C2α expression is required for genomic stability. Reduced abundance of PI3K-C2α in breast cancer models initially impairs tumor growth but later leads to the convergent evolution of fast-growing clones with mitotic checkpoint defects. As a consequence of altered spindle, loss of PI3K-C2α increases sensitivity to taxane-based therapy in pre-clinical models and in neoadjuvant settings.

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Sigma-Aldrich
Nocodazole, ≥99% (TLC), powder
Sigma-Aldrich
Z-Leu-Leu-Leu-al, ≥90% (HPLC)
Sigma-Aldrich
PIK3C2A, active, GST tagged human, PRECISIO®, recombinant, expressed in baculovirus infected Sf9 cells, ≥70% (SDS-PAGE), buffered aqueous glycerol solution

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