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The multi-targeted kinase inhibitor sunitinib induces apoptosis in colon cancer cells via PUMA

Sun, J and Sun, Q and Brown, MF and Dudgeon, C and Chandler, J and Xu, X and Shu, Y and Zhang, L and Yu, J (2012) The multi-targeted kinase inhibitor sunitinib induces apoptosis in colon cancer cells via PUMA. PLoS ONE, 7 (8).

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Abstract

Constitutive activation of pro-survival kinases has become a promising target of small molecules with an increasing interest in developing multi-targeted agents. The mechanisms underlying the responsiveness to most agents targeting cancer specific survival pathways are still poorly understood but critical for their clinical application. In this study, we found that sunitinib, a small molecule inhibitor of multiple tyrosine kinases including VEGFRs and PDGFRs induces apoptosis and inhibits cell growth in colon cancer cells in cell culture and xenograft models via the BH3-only protein PUMA. Sunitinib treatment induced PUMA transcription via the AKT/FoxO3a axis. PUMA, BH3 mimetics, or 5-Flurourical sensitized colon cancer cells to sunitinib-induced apoptosis. Furthermore, PUMA was induced by sunitinib treatment in xenograft tumors, and deficiency in PUMA significantly suppressed the anti-tumor effects of sunitinib. Our study suggests that PUMA-mediated apoptosis is important for the therapeutic responses to sunitinib, and activation of the mitochondrial pathway by BH3 mimetics or PUMA manipulation may be useful for improving the antitumor activity of sunitinib. Modulation of PUMA and selective Bcl-2 family members might be potential biomarkers for predicting sunitinib responses. © 2012 Sun et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Sun, J
Sun, Qqus4@pitt.eduQUS4
Brown, MF
Dudgeon, C
Chandler, J
Xu, X
Shu, Y
Zhang, Lliz22@pitt.eduLIZ22
Yu, Jjiy3@pitt.eduJIY3
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorCheng, Jin QUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Centers: Other Centers, Institutes, or Units > Pittsburgh Cancer Institute
Date: 17 August 2012
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 7
Number: 8
DOI or Unique Handle: 10.1371/journal.pone.0043158
Schools and Programs: School of Medicine > Pathology
School of Medicine > Pharmacology and Chemical Biology
Refereed: Yes
Other ID: NLM PMC3422222
PubMed Central ID: PMC3422222
PubMed ID: 22912816
Date Deposited: 18 Oct 2012 20:51
Last Modified: 03 Feb 2019 07:55
URI: http://d-scholarship.pitt.edu/id/eprint/15888

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