Destruction of a Microtubule-Bound MYC Reservoir during Mitosis Contributes to Vincristine's Anticancer Activity.

Autor:	Becker S; Department of Hematology and Medical Oncology, University Medicine Goettingen, Goettingen, Germany., Kiecke C; Department of Hematology and Medical Oncology, University Medicine Goettingen, Goettingen, Germany., Schäfer E; Department of Hematology and Medical Oncology, University Medicine Goettingen, Goettingen, Germany., Sinzig U; Department of Hematology and Medical Oncology, University Medicine Goettingen, Goettingen, Germany., Deuper L; Department of Hematology and Medical Oncology, University Medicine Goettingen, Goettingen, Germany., Trigo-Mourino P; Max-Planck Institute for Biophysical Chemistry, Goettingen, Germany.; Analytical Research and Development, Merck & Co., Inc., Kenilworth, New Jersey., Griesinger C; Max-Planck Institute for Biophysical Chemistry, Goettingen, Germany., Koch R; Department of Hematology and Medical Oncology, University Medicine Goettingen, Goettingen, Germany., Rydzynska Z; Department of Hematology and Medical Oncology, University Medicine Goettingen, Goettingen, Germany., Chapuy B; Department of Hematology and Medical Oncology, University Medicine Goettingen, Goettingen, Germany., von Bonin F; Department of Hematology and Medical Oncology, University Medicine Goettingen, Goettingen, Germany., Kube D; Department of Hematology and Medical Oncology, University Medicine Goettingen, Goettingen, Germany., Venkataramani V; Department of Hematology and Medical Oncology, University Medicine Goettingen, Goettingen, Germany., Bohnenberger H; Institute of Pathology, University Medicine Goettingen, Goettingen, Germany., Leha A; Department of Medical Statistics, University Medicine Goettingen, Goettingen, Germany., Flach J; Department of Hematology and Medical Oncology, University Medicine Goettingen, Goettingen, Germany., Dierks S; Department of Hematology and Medical Oncology, University Medicine Goettingen, Goettingen, Germany., Bastians H; Department of Experimental Oncology, University Medicine Goettingen, Goettingen, Germany., Maruschak B; Institute for Neuropathology, University Medicine Goettingen, Goettingen, Germany., Bojarczuk K; Department of Hematology and Medical Oncology, University Medicine Goettingen, Goettingen, Germany.; Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland., Taveira MO; Department of Medicine, BIDMC/Harvard Medical School, Boston, Massachusetts., Trümper L; Department of Hematology and Medical Oncology, University Medicine Goettingen, Goettingen, Germany., Wulf GM; Department of Medicine, BIDMC/Harvard Medical School, Boston, Massachusetts., Wulf GG; Department of Hematology and Medical Oncology, University Medicine Goettingen, Goettingen, Germany. gerald.wulf@med.uni-goettingen.de.
Jazyk:	angličtina
Zdroj:	Molecular cancer research : MCR [Mol Cancer Res] 2020 Jun; Vol. 18 (6), pp. 859-872. Date of Electronic Publication: 2020 Mar 11.
DOI:	10.1158/1541-7786.MCR-19-1203
Abstrakt:	Tightly regulated activity of the transcription factor MYC is essential for orderly cell proliferation. Upon deregulation, MYC elicits and promotes cancer progression. Proteasomal degradation is an essential element of MYC regulation, initiated by phosphorylation at Serine62 (Ser62) of the MB1 region. Here, we found that Ser62 phosphorylation peaks in mitosis, but that a fraction of nonphosphorylated MYC binds to the microtubules of the mitotic spindle. Consequently, the microtubule-destabilizing drug vincristine decreases wild-type MYC stability, whereas phosphorylation-deficient MYC is more stable, contributing to vincristine resistance and induction of polyploidy. PI3K inhibition attenuates postmitotic MYC formation and augments the cytotoxic effect of vincristine. IMPLICATIONS: The spindle's function as a docking site for MYC during mitosis may constitute a window of specific vulnerability to be exploited for cancer treatment. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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