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Tumor Biology

, Volume 37, Issue 7, pp 9169–9179 | Cite as

The proliferation impairment induced by AQP3 deficiency is the result of glycerol uptake and metabolism inhibition in gastric cancer cells

  • Zheng Li
  • Bowen Li
  • Lei Zhang
  • Liang Chen
  • Guangli Sun
  • Qun Zhang
  • Jiwei Wang
  • Xiaofei Zhi
  • Linjun Wang
  • Zekuan Xu
  • Hao Xu
Original Article

Abstract

Gastric cancer is a big threat to human health. Effective therapeutic cancer target remains to be discovered. Aquaporin 3 (AQP3) belongs to a family of transmembrane channels that are important in transporting water, glycerol, and other small molecules across the cell membrane. Glycerol that is transported by AQP3 is necessary for cell energy generation and lipid synthesis which fulfill the cell biological processes. Previous studies have shown that AQP3 is implicated in disease progression in several cancer types. However, whether AQP3-regulated glycerol uptake and metabolism were involved in cancer progression remains to be further studied. Our study demonstrated that the expression of AQP3 was positively correlated with glycerol level in human gastric cancer tissues. AQP3 inhibition induced proliferation impairment in gastric cancer cells both in vitro and in vivo. AQP3 inhibition that induced glycerol uptake reduction and glycerol administration would rehabilitate the cell proliferation. The energy and lipid production decreased when AQP3 was knocked down since the cellular glycerol level and several lipogenesis enzymes were downregulated. PI3K/Akt signaling pathway, which was involved in the impaired lipid and ATP production, was also inhibited after AQP3 knockdown. Our study indicated that the energy and lipid production inhibition, which were responsible for gastric cancer cell proliferation impairment, were induced by glycerol uptake reduction after AQP3 knockdown.

Keywords

AQP3 Glycerol Proliferation ATP Lipogenesis 

Abbreviations

AQP3

Aquaporin 3

GYK

Glycerol kinase

G3P

Glycerol-3-phosphate

MAG

Monoglyceride

DAG

Dialyceride

TAG

Triglyceride

PA

Phosphatidic acid

LPA

Lysophosphatidic acid

AGPAT1, 2, and 3

1-Acylglycerol-3-phosphate O-acyltransferase 1, 2, and 3

GPAT1 and 2

Glycerol-3-phosphate acyltransferase 1 and 2

MOGAT1 and 2

Monoacylglycerol O-acyltransferase 1 and 2

DGAT1 and 2

Diacylglycerol O-acyltransferase 1 and 2

FFA

Free fatty acid

FAO

Fatty acid oxidation

FA

Fatty acid

RT

Room temperature

Notes

Acknowledgements

Our work was sponsored by the Natural Science Foundation of China (30901421), the Natural Science Foundation of Jiangsu Province of China (BK20141493), and the Program for Development of Innovative Research Team in the First Affiliated Hospital of NJMU.

Compliance with ethical standards

Conflicts of interest

None

Ethics approval

The Institutional Ethical Board of the First Affiliated Hospital of Nanjing Medical University approved of our study. Human samples were taken after informed contents be signed. For animal experiments, our designs were in line with the institutional animal care and use committee guidelines.

References

  1. 1.
    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.CrossRefPubMedGoogle Scholar
  2. 2.
    Agre P, Kozono D. Aquaporin water channels: molecular mechanisms for human diseases. FEBS Letters. 2003;555:72–8.CrossRefPubMedGoogle Scholar
  3. 3.
    Verkman AS, Mitra AK. Structure and function of aquaporin water channels. Am J Physiol Renal Physiol. 2000;278:F13–28.PubMedGoogle Scholar
  4. 4.
    Fujiyoshi Y, Mitsuoka K, de Groot BL, Philippsen A, Grubmuller H, Agre P, et al. Structure and function of water channels. Curr Opin Struct Biol. 2002;12:509–15.CrossRefPubMedGoogle Scholar
  5. 5.
    Matsuzaki T, Tajika Y, Ablimit A, Aoki T, Hagiwara H, Takata K. Aquaporins in the digestive system. Medical Electron Microscopy. 2004;37:71–80.CrossRefPubMedGoogle Scholar
  6. 6.
    Zhi X, Tao J, Li Z, Jiang B, Feng J, Yang L, et al. Mir-874 promotes intestinal barrier dysfunction through targeting aqp3 following intestinal ischemic injury. FEBS Letters. 2014;588:757–63.CrossRefPubMedGoogle Scholar
  7. 7.
    Wang G, Gao F, Zhang W, Chen J, Wang T, Zhang G, et al. Involvement of aquaporin 3 in helicobacter pylori-related gastric diseases. PloS one. 2012;7, e49104.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Verkman AS, Hara-Chikuma M, Papadopoulos MC. Aquaporins—new players in cancer biology. Journal of Molecular Medicine. 2008;86:523–9.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Wang J, Feng L, Zhu Z, Zheng M, Wang D, Chen Z, et al. Aquaporins as diagnostic and therapeutic targets in cancer: how far we are? J Transl Med. 2015;13:96.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Huang YH, Zhou XY, Wang HM, Xu H, Chen J, Lv NH. Aquaporin 5 promotes the proliferation and migration of human gastric carcinoma cells. Tumour Biology. 2013;34:1743–51.CrossRefPubMedGoogle Scholar
  11. 11.
    Shi X, Wu S, Yang Y, Tang L, Wang Y, Dong J, et al. Aqp5 silencing suppresses p38 mapk signaling and improves drug resistance in colon cancer cells. Tumour Biology. 2014;35:7035–45.CrossRefPubMedGoogle Scholar
  12. 12.
    Wei M, Shi R, Zeng J, Wang N, Zhou J, Ma W. The over-expression of aquaporin-1 alters erythroid gene expression in human erythroleukemia k562 cells. Tumour Biology. 2015;36:291–302.CrossRefPubMedGoogle Scholar
  13. 13.
    Zhao H, Yang X, Zhou Y, Zhang W, Wang Y, Wen J, et al. Potential role of aquaporin 3 in gastric intestinal metaplasia. Oncotarget. 2015.Google Scholar
  14. 14.
    Swinnen JV, Van Veldhoven PP, Timmermans L, De Schrijver E, Brusselmans K, Vanderhoydonc F, et al. Fatty acid synthase drives the synthesis of phospholipids partitioning into detergent-resistant membrane microdomains. Biochemical and Biophysical Research Communications. 2003;302:898–903.CrossRefPubMedGoogle Scholar
  15. 15.
    Zheng H, Liu W, Anderson LY, Jiang QX. Lipid-dependent gating of a voltage-gated potassium channel. Nature Communications. 2011;2:250.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Moreno-Sanchez R, Rodriguez-Enriquez S, Marin-Hernandez A, Saavedra E. Energy metabolism in tumor cells. FEBS J. 2007;274:1393–418.CrossRefPubMedGoogle Scholar
  17. 17.
    Mazurek S, Boschek CB, Eigenbrodt E. The role of phosphometabolites in cell proliferation, energy metabolism, and tumor therapy. J Bioenerg Biomembr. 1997;29:315–30.CrossRefPubMedGoogle Scholar
  18. 18.
    Brisson D, Vohl MC, St-Pierre J, Hudson TJ, Gaudet D. Glycerol: a neglected variable in metabolic processes? Bioessays. 2001;23:534–42.CrossRefPubMedGoogle Scholar
  19. 19.
    Baba H, Zhang XJ, Wolfe RR. Glycerol gluconeogenesis in fasting humans. Nutrition. 1995;11:149–53.PubMedGoogle Scholar
  20. 20.
    Lass A, Zimmermann R, Oberer M, Zechner R. Lipolysis—a highly regulated multi-enzyme complex mediates the catabolism of cellular fat stores. Prog Lipid Res. 2011;50:14–27.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Cui G, Staron MM, Gray SM, Ho PC, Amezquita RA, Wu J, et al. Il-7-induced glycerol transport and TAG synthesis promotes memory CD8+ T cell longevity. Cell. 2015;161:750–61.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Naidoo K, Coetzer TL. Reduced glycerol incorporation into phospholipids contributes to impaired intra-erythrocytic growth of glycerol kinase knockout plasmodium falciparum parasites. Biochim Biophys Acta. 1830;2013:5326–34.Google Scholar
  23. 23.
    Wang C, Chi Y, Li J, Miao Y, Li S, Su W, et al. Fam3a activates pi3k p110alpha/akt signaling to ameliorate hepatic gluconeogenesis and lipogenesis. Hepatology. 2014;59:1779–90.CrossRefPubMedGoogle Scholar
  24. 24.
    Lee N, Kim I, Park S, Han D, Ha S, Kwon M, et al. Creatine inhibits adipogenesis by downregulating insulin-induced activation of the phosphatidylinositol 3-kinase signaling pathway. Stem Cells Dev. 2015;24:983–94.CrossRefPubMedGoogle Scholar
  25. 25.
    Shaik ZP, Fifer EK, Nowak G. Akt activation improves oxidative phosphorylation in renal proximal tubular cells following nephrotoxicant injury. Am J Physiol Renal Physiol. 2008;294:F423–432.CrossRefPubMedGoogle Scholar
  26. 26.
    Davila D, Fernandez S, Torres-Aleman I. Astrocyte resilience to oxidative stress induced by insulin like growth factor I (IGF-I) involves preserved AKT (protein kinase B) activity. The Journal of Biological Chemistry. 2015.Google Scholar
  27. 27.
    Mata R, Palladino C, Nicolosi ML, Presti AR, Malaguarnera R, Ragusa M, et al. IGF-I induces upregulation of DDR1 collagen receptor in breast cancer cells by suppressing MIR-199a-5p through the PI3K/AKT pathway. Oncotarget. 2015.Google Scholar
  28. 28.
    Rodriguez A, Catalan V, Gomez-Ambrosi J, Fruhbeck G. Aquaglyceroporins serve as metabolic gateways in adiposity and insulin resistance control. Cell Cycle. 2011;10:1548–56.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Hara-Chikuma M, Verkman AS. Prevention of skin tumorigenesis and impairment of epidermal cell proliferation by targeted aquaporin-3 gene disruption. Molecular and Cellular Biology. 2008;28:326–32.CrossRefPubMedGoogle Scholar
  30. 30.
    Chen J, Wang T, Zhou YC, Gao F, Zhang ZH, Xu H, et al. Aquaporin 3 promotes epithelial-mesenchymal transition in gastric cancer. J Exp Clin Cancer Res. 2014;33:38.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Xu H, Xu Y, Zhang W, Shen L, Yang L, Xu Z. Aquaporin-3 positively regulates matrix metalloproteinases via PI3K/AKT signal pathway in human gastric carcinoma SGC7901 cells. J Exp Clin Cancer Res. 2011;30:86.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Medes G, Thomas A, Weinhouse S. Metabolism of neoplastic tissue. IV. A study of lipid synthesis in neoplastic tissue slices in vitro. Cancer Research. 1953;13:27–9.PubMedGoogle Scholar
  33. 33.
    Abramson HN. The lipogenesis pathway as a cancer target. J Med Chem. 2011;54:5615–38.CrossRefPubMedGoogle Scholar
  34. 34.
    Cantor JR, Sabatini DM. Cancer cell metabolism: one hallmark, many faces. Cancer Discov. 2012;2:881–98.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Boroughs LK, DeBerardinis RJ. Metabolic pathways promoting cancer cell survival and growth. Nat Cell Biol. 2015;17:351–9.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Rojek AM, Skowronski MT, Fuchtbauer EM, Fuchtbauer AC, Fenton RA, Agre P, et al. Defective glycerol metabolism in aquaporin 9 (aqp9) knockout mice. Proceedings of the National Academy of Sciences of the United States of America. 2007;104:3609–14.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Oronsky BT, Oronsky N, Fanger GR, Parker CW, Caroen SZ, Lybeck M, et al. Follow the atp: tumor energy production: a perspective. Anticancer Agents Med Chem. 2014;14:1187–98.CrossRefPubMedGoogle Scholar
  38. 38.
    Shi Y, Cheng D. Beyond triglyceride synthesis: the dynamic functional roles of MGAT and DGAT enzymes in energy metabolism. Am J Physiol Endocrinol Metab. 2009;297:E10–18.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Athenstaedt K, Daum G. The life cycle of neutral lipids: synthesis, storage and degradation. Cell Mol Life Sci. 2006;63:1355–69.CrossRefPubMedGoogle Scholar
  40. 40.
    Watt MJ, Steinberg GR. Regulation and function of triacylglycerol lipases in cellular metabolism. The Biochemical Journal. 2008;414:313–25.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Zheng Li
    • 1
  • Bowen Li
    • 1
  • Lei Zhang
    • 1
  • Liang Chen
    • 1
  • Guangli Sun
    • 1
  • Qun Zhang
    • 1
  • Jiwei Wang
    • 1
  • Xiaofei Zhi
    • 2
  • Linjun Wang
    • 1
    • 3
  • Zekuan Xu
    • 1
  • Hao Xu
    • 1
  1. 1.Department of General SurgeryThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
  2. 2.Department of General SurgeryThe Affiliated Hospital of Nantong UniversityNantongChina
  3. 3.Department of General SurgeryThe People’s Hospital of TaizhouTaizhouChina

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