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Roles of TGFβ1 in the expression of phosphoinositide 3-kinase isoform genes and sensitivity and response of lung telocytes to PI3K inhibitors

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Abstract

Background

The mouse lung telocyte cell line (TCSV40) recently established provides further opportunities to learn TC biology and functions. The present study aims at investigating regulatory roles of phosphoinositide 3-kinase (PI3K) isoforms in TC proliferation and movement and in TGFβ1-induced sensitivity and response of lung TCs to PI3K inhibitors.

Materials and methods

Network and molecular interactions of genes coding PI3K family or TGFβ family proteins in mouse primary TCs were defined. Mouse lung TCSV40 proliferation, apoptosis, cell cycle, and dynamical bio-behaviors were measured with or without TGFβ1 stimulation or PI3K catalytic isoform protein (PI3K/mTOR, PI3Kα/δ/β, PI3K p110δ, or pan-PI3K) inhibitions.

Results

The present study showed the difference of network characteristics and interactions of genes coding PI3K isoform proteins or TGFβ family proteins in primary lung telocytes from mouse lungs compared to those of other cells residing in the lung. TGFβ1 had diverse effects on TC proliferation with altered TC number in G2 or S phase, independent upon the administered dose of TGFβ1. PI3Kα/δ/β, PI3K/mTOR, and PI3K p110δ were involved in TC proliferation, of which PI3Kα/δ/β was more sensitive. The effects of pan-PI3K inhibitor indicate that more PI3K isoforms were stimulated by the administering of external TGFβ1 and contributed to TGFβ1-induced TC proliferation. PI3K p110δ upregulated TC proliferation and movement dynamically without TGFβ1, and downregulated TC proliferation with TGFβ1 stimulation, but not TC movement. PI3Kα/δ/β and PI3K/mTOR were more active in TGFβ1-induced S phase accumulation and had similar dynamic effects to PI3K p110δ. Gene expression of PI3K isoforms in TCs was upregulated after TGFβ1 stimulation. The expression of PIK3CA coding p110-α or PIK3CG coding p110-γ were up- or downregulated in TCs without TGFβ1, respectively, when PI3K/mTOR, PI3Kα/δ/β, PI3K p110δ, or pan-PI3K were inhibited. TGFβ1 upregulated the expression of PIK3CA and PIK3CB, while downregulated the expression of PIK3CD and PIK3CG.

Conclusion

Our data imply that TGFβ1 plays divergent roles in the expression of PI3K isoform genes in lung TCs and can alter the sensitivity and response of lung TCs to PI3K inhibitors.

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Abbreviations

PI3K:

phosphatidylinositol 3 -kinase

PDK-1:

phosphoinositide-dependent protein kinase-1

PACs:

proximal airway cells

CD8+ T-LL CD8+ T:

cells from lung

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Funding

The work was financially supported by grants from the National Natural Science Foundation of China (81700008), the Zhongshan Distinguished Professor Grant (XDW), the National Nature Science Foundation of China (91230204, 81270099, 81320108001, 81270131, 81300010, 81700008, 81873409), the Shanghai Committee of Science and Technology (12JC1402200, 12431900207, 11410708600, 14431905100), the operation funding of Shanghai Institute of Clinical Bioinformatics, Ministry of Education for Academic Special Science and Research Foundation for PhD Education (20130071110043), and National Key Research and Development Program (2016YFC0902400, 2017YFSF090207, 2017YFC0909500).

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Authors and Affiliations

  1. Zhongshan Hospital Institute for Clinical Science, Shanghai Institute of Clinical Bioinformatics, Shanghai Engineering Research for AI Technology for Cardiopulmonary Diseases, Jinshan Hospital Center for Tumor Diagnosis & Therapy, Shanghai Medical College, Fudan University, Shanghai, China

    Dongli Song, Li Tang, Lu Wang, Jianan Huang & Xiangdong Wang

  2. Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

    Tao Zeng

  3. Department of Anesthesiology, Zhongshan Hospital, Department of Anesthesiology, Minhang Branch, Zhongshan Hospital, Fudan University, Shanghai, China

    Hao Fang

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  1. Dongli Song
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  2. Li Tang
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  3. Lu Wang
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  4. Jianan Huang
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  5. Tao Zeng
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  6. Hao Fang
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  7. Xiangdong Wang
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Contributions

DS designed the study and completed the experimental process, literature search, and generation of figures. DS, HF, and XW wrote and edited the manuscript. DS, LW, LT, JNH, TZ, and HF completed the generation of figures. All authors reviewed the manuscript. All authors read and approved the final manuscript.

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Correspondence to Hao Fang or Xiangdong Wang.

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Supplement Figure 1:

The effects of PI3K inhibitors on the differentiation of TCSV40 after stimulation with TGFβ1. A-D. Analysis of TCSV40 differentiation with the treatment of PI3K inhibitors. E-H. Analysis of TCSV40 differentiation with the treatment of PI3K inhibitors and stimulation with TGFβ1, n = 6-8, *P < 0.05 vs. TCSV40. #P < 0.05 vs. 5 ng/ml TGFβ1 treated TCSV40. (PNG 132 kb)

Supplement Figure 2:

The effects of PI3K inhibitors on the death of TCSV40 after stimulation with TGFβ1. A-D. Analysis of TCSV40 death with the treatment of PI3K inhibitors. E-H. Analysis of TCSV40 death with the treatment of PI3K inhibitors and stimulation with TGFβ1, n = 6-8, *P < 0.05 vs. TCSV40. #P < 0.05 vs. 5 ng/ml TGFβ1 treated TCSV40. (PNG 133 kb)

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Song, D., Tang, L., Wang, L. et al. Roles of TGFβ1 in the expression of phosphoinositide 3-kinase isoform genes and sensitivity and response of lung telocytes to PI3K inhibitors. Cell Biol Toxicol 36, 51–64 (2020). https://doi.org/10.1007/s10565-019-09487-3

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