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Targeting anaphase catastrophe through CDK inhibition in lung cancer / by Shanhu Hu

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Author	Hu, Shanhu
Title	Targeting anaphase catastrophe through CDK inhibition in lung cancer / by Shanhu Hu
Date	2015
Abstract	Aneuploidy is frequently detected in human cancers and is implicated in carcinogenesis. Pharmacological targeting of aneuploidy is an attractive therapeutic strategy, as this would preferentially eliminate malignant over normal cells. Our prior work discovered that CDK2 inhibition causes aneuploid lung cancer cells to undergo multipolar cell division, followed by apoptosis and reduced growth, defined as anaphase catastrophe. Cells with activating KRAS mutations were especially sensitive to CDK2 inhibition. This thesis was undertaken to investigate the mechanisms of CDK-mediated anaphase catastrophe and how activated KRAS enhances lung cancer cells sensitivity to CDK inhibition. Live-cell imaging provided direct evidence that following CDK inhibition, lung cancer cells develop multipolar anaphase and undergo multipolar cell division with the resulting progeny apoptotic. Pan-CDK-inhibitor dinaciclib treatment and genetic knockdown experiments implicated inhibition of CDK1 and CDK2, but not CDK9 in mediating anaphase catastrophe in lung cancer cells. Small interfering RNA (siRNA)-mediated repression of the CDK1/2 target centrosomal protein CP110 induced anaphase catastrophe, while CP110 overexpression antagonized CDK inhibitor-mediated anaphase catastrophe of lung cancer cells. Site-direct mutagenesis revealed critical CDK phosphorylation sites of CP110 in mediating anaphase catastrophe by affecting centrosome clustering in mitosis. Moreover, activated KRAS mutations sensitized lung cancer cells to CDK inhibition by downregulating CP110 expression through accelerating its degradation rates via the upregulation of one of CP110 ubiquitin ligases, SCFCyclin F. Finally, lung cancer cells sensitivity to CDK inhibition was enhanced by combining it with deubiquitinase USP33 knockdown that also accelerates CP110 degradation. Translational relevance of these findings was established by examination of murine and human paired normal-malignant lung tissues. Marked upregulation of CP110 in malignant versus normal lung was detected. Furthermore, human lung cancers with KRAS mutations had significantly lower CP110 expression as compared to KRAS wild-type cancers. This thesis revealed that CP110 plays a critical mechanistic role in the response of lung cancer cells to CDK inhibition, especially in the presence of activated KRAS mutations. Moreover, a novel therapeutic strategy of combining CDK2 inhibition with repression of CP110 levels through USP33 depletion or antagonism proposed to improve clinical treatment outcomes for lung cancers. These studies provided further rationale to investigate CDK inhibitors in lung cancer therapies.
Description	1 online resource (xix, 197 leaves) : illustrations (some color)
Format	application/pdf
College	Dartmouth College -- Experimental and Molecular Medicine Program. Geisel School of Medicine at Dartmouth.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.1623

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