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29 January 2019 : Laboratory Research  

Metformin Inhibit Lung Cancer Cell Growth and Invasion in Vitro as Well as Tumor Formation in Vivo Partially by Activating PP2A

Xiaohu Zhou1AB, Shanshan Liu2BE, Xuemei Lin1CD, Liping Xu1DF, Xiaoming Mao1CE, Jun Liu1EF, Zixing Zhang1BE, Wenhong Jiang1FG, Hua Zhou3A*

DOI: 10.12659/MSM.912059

Med Sci Monit 2019; 25:836-846

Abstract

BACKGROUND: The aim of this study was to investigate whether PP2A activation is involved in the anti-cancer activity of metformin.

MATERIAL AND METHODS: A549 and H1651 human lung cancer cells were constructed with stable a4 overexpression (O/E α4) or knockdown of PP2A catalytic subunit A/B(sh-PP2Ac). Influences of okadaic acid (OA) treatment, O/E α4 or sh-PP2Ac on metformin treated cells were investigated by cell viability, proliferation, apoptosis, and Transwell invasion assay in vitro. Protein expression levels of Bax, Bcl-2, Myc, and Akt as well as serine phosphorylation level of Bax, Myc, and Akt were examined by western blot. For in vivo assays, wild type (WT) or modified A549 cells were subcutaneously injected in nude mice, and metformin treatment on these xenografted tumors were assayed by tumor formation assay and western blot detecting cell proliferation marker PCNA (proliferating cell nuclear antigen) as well as protein expression level and serine phosphorylation level of Akt and Myc.

RESULTS: Metformin treatment significantly reduced A549 or H1651 cell growth and invasive capacity in vitro as well as Ser184 phosphorylation of Bax, Ser62 phosphorylation of Myc, and Ser473 phosphorylation of Akt, all of which could be partially attenuated by OA treatment, O/E α4 or sh-PP2Ac. Metformin treatment also significantly reduced tumor formation in vivo as well as protein expression of PCNA, Akt, Myc, and serine phosphorylation of the latter 2, which can be partially blocked by O/E α4 or sh-PP2Ac.

CONCLUSIONS: Metformin reduced lung cancer cell growth and invasion in vitro as well as tumor formation in vivo partially by activating PP2A.

Keywords: Metformin, Mycolic Acids, Phosphorylation, A549 cells, Cell Cycle, Genes, bcl-2, Genes, myc, Protein Phosphatase 2, Proto-Oncogene Proteins c-akt, bcl-2-Associated X Protein

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750