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. 2018 Apr 11;18(1):407.
doi: 10.1186/s12885-018-4224-x.

Bexarotene inhibits the viability of non-small cell lung cancer cells via slc10a2/PPARγ/PTEN/mTOR signaling pathway

Xinghao Ai  1   2 , Feng Mao  2 , Shengping Shen  2 , Yang Shentu  2 , Jiejun Wang  3 , Shun Lu  4
Affiliations

Bexarotene inhibits the viability of non-small cell lung cancer cells via slc10a2/PPARγ/PTEN/mTOR signaling pathway

Xinghao Ai et al. BMC Cancer. .

Abstract

Background: Thirty to 40 % of non-small cell lung cancer (NSCLC) patients developed higher hypertriglyceridemia in the process of treatment with bexarotene. And bioinformatics studies discovered that the expression of slc10a2 was increased in high-grade hypertriglyceridemia patients. So, we will explore the mechanism which may involve in this process.

Methods: We constructed slc10a2 overexpressed A549 cells and H1299 cells as cell models, normal A549 cells and H1299 cells as control. Then we explored the effects of slc10a2 on A549 cells and H1299 cells behaviors, including proliferation, invasion and apoptosis. The expression of apoptotic related genes and anti-cancer genes also been detected.

Results: We found that the proliferation and migration were inhibited and the apoptosis of NSCLC cells was accelerated by bexarotene. In addition, overexpressed slc10a2 in NSCLC cells can further suppress the proliferation and migration, and promote apoptosis under the treatment of bexarotene. On the contrary, the opposite results were obtained after slc10a2 gene was silenced in NSCLC cells treated with bexarotene. Moreover, the expression of caspase 3, caspase 7, PTEN, P21, P53, LKB1, TSC2 were increased and the expression of Bcl-2, cyclin D1, c-FLIP were declined in NSCLC cells and slc10a2 overexpressed NSCLC cells with the treatment of bexarotene, and the opposite situations were seen after slc10a2 gene was silenced in NSCLC cells. The further studies revealed the increased expression of slc10a2 activated the expression of peroxisome proliferator-activated receptor γ (PPARγ), then up-regulated PTEN expression and down-regulated mTOR expression.

Conclusion: These results suggest that bexarotene inhibits the viability of lung cancer cells via slc10a2/PPARγ/PTEN/mTOR signaling pathway.

Keywords: A549 cells; Bexarotene; H1299 cells; Non-small cell lung cancer; PPARγ; slc10a2.

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Figures

Scheme 1
Scheme 1
The chemical structure of bexarotene
Fig. 1
Fig. 1
The construction and identification of slc10a2 overexpressed A549 cells. a The immunofluorescence staining showed slc10a2 gene had successfully transfected into 293 T cells; b The immunofluorescence staining showed slc10a2 overexpressed A549 cells were successfully constructed; c The expression of slc10a2 was significant higher in slc10a2 overexpressed A549 cells than in A549 cells; d Slc10a2-shRNA can effectively inhibit the expression of slc10a2 in A549 cells. All experiments were repeated 3 times
Fig. 2
Fig. 2
The proliferation of A549 cells treated with bexarotene, bexarotene + slc10a2-shRNA, bexarotene + slc10a2-overexpression respectively. A549 cells without treatment as control. All experiments were repeated 3 times
Fig. 3
Fig. 3
The effects of slc10a2 on invasion of A549 cells treated with bexarotene. a The invasion behavior of A549 cells treated with bexarotene, bexarotene + slc10a2-shRNA, bexarotene + slc10a2-overexpression respectively, A549 cells without any treatment as control group. b The quantification of migratory A549 cells treated with bexarotene, bexarotene + slc10a2-shRNA, bexarotene + slc10a2-overexpression respectively. All experiments were repeated 3 times. ***p < 0.001
Fig. 4
Fig. 4
The effects of slc10a2 on apoptosis of A549 cells treated with bexarotene. a The apoptosis rate of A549 cells treated with 0.1 mM bexarotene, overexpressed slc10a2 in combination with 0.1 mM bexarotene, slc10a2-shRNA in combination with 0.1 mM bexarotene respectively; b The apoptosis rate of A549 cells treated with 1 mM bexarotene, overexpressed slc10a2 in combination with 1 mM bexarotene, slc10a2-shRNA in combination with 1 mM bexarotene respectively; c The apoptosis rate of A549 cells treated with 10 mM bexarotene, overexpressed slc10a2 in combination with 10 mM bexarotene, slc10a2-shRNA in combination with 10 mM bexarotene respectively, A549 cells without any treatment as control group (d). All experiments were repeated 3 times
Fig. 5
Fig. 5
The effects of slc10a2 on expression of apoptosis related genes in A549 cells treated with bexarotene. a The expression of apoptotic related genes Bcl-2, cyclin D1, c-FLIP, caspase 3, caspase 7 in A549 cells treated with bexarotene, overexpressed slc10a2 in combination with bexarotene, slc10a2-shRNA in combination with bexarotene respectively, A549 cells without any treatment as control group. b The expression of tumor suppressor genes PTEN, P21, P53, LKB1, TSC2 in A549 cells treated with bexarotene, overexpressed slc10a2 in combination with bexarotene, slc10a2-shRNA in combination with bexarotene respectively, A549 cells without any treatment as control group. All experiments were repeated 3 times
Fig. 6
Fig. 6
Slc10a2 via PPARγ plays an important role in the proliferation of A549 cells with the treatment of bexarotene. a The proliferation rate of A549 cells treated with bexarotene, bexarotene in combination with GW9662 respectively, A549 cells without any treatment as control group. b The proliferation rate of slc10a2 overexpressed A549 cells treated with bexarotene, bexarotene in combination with GW9662 respectively, A549 cells without any treatment as control group. All experiments were repeated 3 times
Fig. 7
Fig. 7
Slc10a2 via PPARγ plays an important role in tumor suppressor with the treatment of bexarotene. a The expression of apoptotic related genes Bcl-2, cyclin D1, c-FLIP, caspase 3, caspase 7 in A549 cells and slc10a2 overexpressed A549 cells when treated with bexarotene, bexarotene in combination with GW9662 respectively; b The expression of tumor suppressor genes PTEN, P21, P53, LKB1, TSC2 in A549 cells and slc10a2 overexpressed A549 cells when treated with bexarotene, bexarotene in combination with GW9662 respectively. A549 cells without any treatment as control group. All experiments were repeated 3 times
Fig. 8
Fig. 8
Bexarotene inhibits the viability of A549 cells via slc10a2/PPARγ/PTEN/mTOR signaling pathway. a The expression of slc10a2 and PPARγ in A549 cells treated with 1 mM, 5 mM, 10 mM bexarotene respectively. b The quantification of slc10a2 and PPARγ expression in A549 cells treated with 1 mM, 5 mM, 10 mM bexarotene respectively. c The expression of slc10a2, PTEN, mTOR in A549 cells treated with bexarotene, bexarotene + GW9662 respectively. d The quantification of slc10a2, PTEN, mTOR expression in A549 cells treated with bexarotene, bexarotene + GW9662. All experiments were repeated 3 times. *p < 0.05, **p < 0.01
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