Oncotarget

Research Papers:

BTK suppresses myeloma cellular senescence through activating AKT/P27/Rb signaling

Chunyan Gu, Hailin Peng, Yue Lu, Hongbao Yang, Zhidan Tian, Gang Yin, Wen Zhang, Sicheng Lu, Yi Zhang _ and Ye Yang

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Oncotarget. 2017; 8:56858-56867. https://doi.org/10.18632/oncotarget.18096

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Abstract

Chunyan Gu1,2,3,*, Hailin Peng4,*, Yue Lu5, Hongbao Yang6, Zhidan Tian7, Gang Yin2, Wen Zhang8, Sicheng Lu2, Yi Zhang9 and Ye Yang1,2,10

1The Third Affiliated Hospital, Nanjing University of Chinese Medicine, Nanjing 210023, China

2School of Medicine and Life Science, Nanjing University of Chinese Medicine, Nanjing 210023, China

3Department of Pathology, School of Medicine, University of Iowa, Iowa City, Iowa 52242, USA

4Department of Laboratory Medicine, Taizhou People’s Hospital, Taizhou 225300, China

5Department of Radiation Oncology, Jiangsu Cancer Hospital, Nanjing 210009, China

6Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China

7Department of Pathology, Nanjing First Hospital, Nanjing 210006, China

8Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210029, China

9Department of Burns and Plastic Surgery, Affiliated Hospital of Nantong University, Nantong 226001, China

10Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, China

*These authors have contributed equally to this work

Correspondence to:

Yi Zhang, email: [email protected]

Ye Yang, email: [email protected]

Keywords: multiple myeloma, BTK, senescence, AKT, CGI-1746

Received: February 25, 2017     Accepted: April 04, 2017     Published: May 23, 2017

ABSTRACT

We previously explored the role of BTK in maintaining multiple myeloma stem cells (MMSCs) self-renewal and drug-resistance. Here we investigated the elevation of BTK suppressing MM cellular senescence, a state of irreversible cellular growth arrest. We firstly discovered that an increased expression of BTK in MM samples compared to normal controls by immunohistochemistry (IHC), and significant chromosomal gain in primary samples. In addition, BTK high-expressing MM patients are associated with poor outcome in both Total Therapy 2 (TT2) and TT3 cohorts. Knockdown BTK expression by shRNA induced MM cellular senescence using β-galactosidase (SA-b-gal) staining, cell growth arrest by cell cycle staining and decreased clonogenicity while forcing BTK expression in MM cells abrogated these characteristics. We also validated this feature in mouse embryonic fibroblast cells (MEFs), which showed that elevated BTK expression was resistant to MEF senescence after serial cultivation in vitro. Further mechanism study revealed that BTK activated AKT signaling leading to down-regulation of P27 expression and hindered RB activity while AKT inhibitor, LY294002, overcame BTK-overexpression induced cellular senescence resistance. Eventually we demonstrated that BTK inhibitor, CGI-1746, induced MM cellular senescence, colony reduction and tumorigenecity inhibition in vivo. Summarily, we designate a novel mechanism of BTK in mediating MM growth, and BTK inhibitor is of great potential in vivo and in vitro suggesting BTK is a promising therapeutic target for MM.


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