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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2018

Open Access 01-12-2018 | Research

Pin1 inhibition exerts potent activity against acute myeloid leukemia through blocking multiple cancer-driving pathways

Authors: Xiaolan Lian, Yu-Min Lin, Shingo Kozono, Megan K. Herbert, Xin Li, Xiaohong Yuan, Jiangrui Guo, Yafei Guo, Min Tang, Jia Lin, Yiping Huang, Bixin Wang, Chenxi Qiu, Cheng-Yu Tsai, Jane Xie, Ziang Jeff Gao, Yong Wu, Hekun Liu, Xiao Zhen Zhou, Kun Ping Lu, Yuanzhong Chen

Published in: Journal of Hematology & Oncology | Issue 1/2018

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Abstract

Background

The increasing genomic complexity of acute myeloid leukemia (AML), the most common form of acute leukemia, poses a major challenge to its therapy. To identify potent therapeutic targets with the ability to block multiple cancer-driving pathways is thus imperative. The unique peptidyl-prolyl cis-trans isomerase Pin1 has been reported to promote tumorigenesis through upregulation of numerous cancer-driving pathways. Although Pin1 is a key drug target for treating acute promyelocytic leukemia (APL) caused by a fusion oncogene, much less is known about the role of Pin1 in other heterogeneous leukemia.

Methods

The mRNA and protein levels of Pin1 were detected in samples from de novo leukemia patients and healthy controls using real-time quantitative RT-PCR (qRT-PCR) and western blot. The establishment of the lentiviral stable-expressed short hairpin RNA (shRNA) system and the tetracycline-inducible shRNA system for targeting Pin1 were used to analyze the biological function of Pin1 in AML cells. The expression of cancer-related Pin1 downstream oncoproteins in shPin1 (Pin1 knockdown) and Pin1 inhibitor all-trans retinoic acid (ATRA) treated leukemia cells were examined by western blot, followed by evaluating the effects of genetic and chemical inhibition of Pin1 in leukemia cells on transformed phenotype, including cell proliferation and colony formation ability, using trypan blue, cell counting assay, and colony formation assay in vitro, as well as the tumorigenesis ability using in vivo xenograft mouse models.

Results

First, we found that the expression of Pin1 mRNA and protein was significantly increased in both de novo leukemia clinical samples and multiple leukemia cell lines, compared with healthy controls. Furthermore, genetic or chemical inhibition of Pin1 in human multiple leukemia cell lines potently inhibited multiple Pin1 substrate oncoproteins and effectively suppressed leukemia cell proliferation and colony formation ability in cell culture models in vitro. Moreover, tetracycline-inducible Pin1 knockdown and slow-releasing ATRA potently inhibited tumorigenicity of U937 and HL-60 leukemia cells in xenograft mouse models.

Conclusions

We demonstrate that Pin1 is highly overexpressed in human AML and is a promising therapeutic target to block multiple cancer-driving pathways in AML.
Appendix
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Metadata
Title
Pin1 inhibition exerts potent activity against acute myeloid leukemia through blocking multiple cancer-driving pathways
Authors
Xiaolan Lian
Yu-Min Lin
Shingo Kozono
Megan K. Herbert
Xin Li
Xiaohong Yuan
Jiangrui Guo
Yafei Guo
Min Tang
Jia Lin
Yiping Huang
Bixin Wang
Chenxi Qiu
Cheng-Yu Tsai
Jane Xie
Ziang Jeff Gao
Yong Wu
Hekun Liu
Xiao Zhen Zhou
Kun Ping Lu
Yuanzhong Chen
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2018
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-018-0611-7

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