PRIMA-1 met  (APR-246) inhibits growth of colorectal cancer cells with different p53 status through distinct mechanisms

Xiao-Lan Li; Jianbiao Zhou; Zit-Liang Chan; Jing-Yuan Chooi; Zhi-Rong Chen; Wee-Joo Chng

doi:10.18632/oncotarget.5385

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Research Papers:

PRIMA-1^met (APR-246) inhibits growth of colorectal cancer cells with different p53 status through distinct mechanisms

Xiao-Lan Li _, Jianbiao Zhou, Zit-Liang Chan, Jing-Yuan Chooi, Zhi-Rong Chen and Wee-Joo Chng

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Oncotarget. 2015; 6:36689-36699. https://doi.org/10.18632/oncotarget.5385

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Abstract

Xiao-Lan Li1,2,*, Jianbiao Zhou1,*, Zit-Liang Chan1, Jing-Yuan Chooi1, Zhi-Rong Chen2, Wee-Joo Chng1,3,4

1Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore 117599, Republic of Singapore

2Department of Gastroenterology, Suzhou Municipal Hospital (Eastern), Suzhou City, Jiangsu Province, 215001, P.R. China

3Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Republic of Singapore

4Department of Hematology-Oncology, National University Hospital, Singapore 119228, Republic of Singapore

*These authors have contributed equally to this work

Correspondence to:

Wee-Joo Chng, e-mail: [email protected]

Zhi-Rong Chen, e-mail: [email protected]

Keywords: colorectal cancer (CRC), p53, tumor suppressor gene (TSG), PRIMA-1^met, targeted therapy

Received: July 14, 2015 Accepted: September 17, 2015 Published: October 01, 2015

ABSTRACT

PRIMA-1^met (APR-246) is a methylated derivative and structural analog of PRIMA-1 (p53 re-activation and induction of massive apoptosis). PRIMA-1^met has been reported to restore both the wild type (wt) structure and function of mutant p53. Here, we show that PRIMA-1^met is highly effective at limiting the growth of CRC cells regardless of p53 status. However, PRIMA-1^met induces robust apoptosis only in CRC cells with mutant p53. Upregulation of Noxa, a proapoptotic molecule, is crucial for PRIMA-1^met mediated activity. In human xenograft model of disease, PRIMA-1^met effectively suppresses CRC tumor growth. Our results uncover distinct mechanisms of PRIMA-1^met in CRC with different p53 status, thus providing a mechanistic rationale to evaluate the clinical efficacy of PRIMA-1^met in CRC patients with different p53 status.

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Research Papers:

PRIMA-1met (APR-246) inhibits growth of colorectal cancer cells with different p53 status through distinct mechanisms

Abstract

PRIMA-1^met (APR-246) inhibits growth of colorectal cancer cells with different p53 status through distinct mechanisms