Oncotarget

Research Papers:

Protein phosphatase Mg2+/Mn2+ dependent 1F promotes smoking-induced breast cancer by inactivating phosphorylated-p53-induced signals

Shih-Hsin Tu, Yin-Ching Lin, Chi-Cheng Huang, Po-Sheng Yang, Hui-Wen Chang, Chien-Hsi Chang, Chih-Hsiung Wu, Li-Ching Chen _ and Yuan-Soon Ho

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Oncotarget. 2016; 7:77516-77531. https://doi.org/10.18632/oncotarget.12717

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Abstract

Shih-Hsin Tu1,2,3, Yin-Ching Lin4, Chi-Cheng Huang1,5,6, Po-Sheng Yang7,8, Hui-Wen Chang9, Chien-Hsi Chang9, Chih-Hsiung Wu1,10, Li-Ching Chen2,3,11, Yuan-Soon Ho4,9,12,13

1Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

2Breast Medical Center, Taipei Medical University Hospital, Taipei, Taiwan

3Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan

4Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan

5School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan

6Breast Center, Cathay General Hospital, Taipei, Taiwan

7Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan

8Department of Medicine, Mackay Medical College, New Taipei City, Taiwan

9Department of Laboratory Medicine, Taipei Medical University Hospital, Taipei, Taiwan

10Department of Surgery, En Chu Kong Hospital, New Taipei City, Taiwan

11Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

12Comprehensive Cancer Center of Taipei Medical University, Taipei, Taiwan

13School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan

Correspondence to:

Li-Ching Chen, email: [email protected]

Yuan-Soon Ho, email: [email protected]

Keywords: protein phosphatase Mg2+/Mn2+ dependent 1F, breast cancer, smoking, α9-nicotinic acetylcholine receptor, p53

Received: August 15, 2016     Accepted: October 04, 2016     Published: October 18, 2016

ABSTRACT

We previously demonstrated that the activation of α9-nicotinic acetylcholine receptor (α9-nAchR) signaling by smoking promotes breast cancer formation. To investigate the downstream signaling molecules involved in α9-nAChR-induced breast tumorigenesis, we used real-time polymerase chain reactions and Western blotting to assess expression of protein phosphatase Mg2+/Mn2+ dependent 1F (PPM1F), a Ser/Thr protein phosphatase, in human breast cancer samples (n=167). Additionally, stable PPM1F-knockdown and -overexpressing cell lines were established to evaluate the function of PPM1F. The phosphatase activity of PPM1F in nicotine-treated cells was assessed through Western blotting, confocal microscopy, and fluorescence resonance energy transfer. Higher levels of PPM1F were detected in the breast cancer tissues of heavy smokers (n=7, 12.8-fold) greater than of non-smokers (n= 28, 6.3-fold) (**p=0.01). In vitro, nicotine induced PPM1F expression, whereas α9-nAChR knockdown reduced the protein expression of PPM1F. A series of biochemical experiments using nicotine-treated cells suggested that the dephosphorylation of p53 (Ser-20) and BAX (Ser-184) by PPM1F is a critical posttranslational modification, as observed in breast cancer patients who were heavy smokers. These observations indicate that PPM1F may be a mediator downstream of α9-nAChR that activates smoking-induced carcinogenic signals. Thus, PPM1F expression could be used for prognostic diagnosis or inhibited for cancer prevention and therapy.


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