Protein phosphatase Mg2+/Mn2+ dependent 1F promotes smoking-induced breast cancer by inactivating phosphorylatedp53- 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, Yuan-Soon Ho

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

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 a9- 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.

Original languageEnglish
Pages (from-to)77516-77531
Number of pages16
JournalOncotarget
Volume7
Issue number47
DOIs
Publication statusPublished - 2016

Keywords

  • Breast cancer
  • P53
  • protein phosphatase Mg/Mn dependent 1F
  • Smoking
  • α9-nicotinic acetylcholine receptor

ASJC Scopus subject areas

  • Oncology

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