Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

PI4KIIα is a novel regulator of tumor growth by its action on angiogenesis and HIF-1α regulation

Oncogene volume 29, pages 2550–2559 (2010)Cite this article

Subjects

Abstract

Tumor growth is the orchestration of various oncogenes and tumor suppressors, and the regulation of these genes offers a rational therapeutic approach to cancer treatment. In this study, we found a new regulator of tumor growth, phosphatidylinositol 4-kinase type IIα (PI4KIIα), the mechanism of which is involved in angiogenesis and hypoxia-inducible factor HIF-1α regulation. Results obtained from a human cancer tissue microarray showed that PI4KIIα protein expression increases markedly in seven types of cancers compared with normal tissues. Suppression of PI4KIIα leads to retarded tumor growth in nude mice. Downregulation of PI4KIIα in cancer cells eliminates tumor cell-induced endothelial cell tubulogenesis and migration, and results in impaired angiogenesis. Further investigation showed that PI4KIIα can directly regulate HIF-1α expression and that the expression of these two proteins is correlated in vivo. At the same time, downregulation of PI4KIIα markedly reduces HER-2 autophosphorylation, and PI4KIIα specifically triggers HIF-1α accumulation through a phosphatidylinositol 3-kinase (PI3K)- and extracellular signal-regulated protein kinase (ERK)-dependent pathway, suggesting that PI4KIIα may regulate HIF-1α through the HER-2/PI3K, ERK cascade. In summary, we discovered a pivotal role for PI4KIIα in the regulation of tumor growth. Our results shed new light on understanding the novel functions of PI4KIIα in cancer and suggest that PI4KIIα may be a promising specific target for tumor therapy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Craige B, Salazar G, Faundez V . (2008). Phosphatidylinositol-4-kinase type II alpha contains an AP-3-sorting motif and a kinase domain that are both required for endosome traffic. Mol Biol Cell 19: 1415–1426.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Di PG, De CP . (2006). Phosphoinositides in cell regulation and membrane dynamics. Nature 443: 651–657.

    Article  Google Scholar 

  • Drabkin D . (1949). The standardization of hemoglobin measurement. Am J Med Sci 217: 710–711.

    CAS  PubMed  Google Scholar 

  • Ferrara N . (2002). VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer 2: 795–803.

    Article  CAS  PubMed  Google Scholar 

  • Folkman J . (1971). Tumor angiogenesis: therapeutic implications. N Engl J Med 285: 1182–1186.

    Article  CAS  PubMed  Google Scholar 

  • Folkman J, Haudenschild C . (1980). Angiogenesis in vitro. Nature 288: 551–556.

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Cardena G, Folkman J . (1998). Is there a role for nitric oxide in tumor angiogenesis? J Natl Cancer Inst 90: 560–561.

    Article  CAS  PubMed  Google Scholar 

  • Gehrmann T, Heilmeyer Jr LM . (1998). Phosphatidylinositol 4-kinases. Eur J Biochem 253: 357–370.

    Article  CAS  PubMed  Google Scholar 

  • Gewinner C, Wang ZC, Richardson A, Teruya-Feldstein J, Etemadmoghadam D, Bowtell D et al. (2009). Evidence that inositol polyphosphate 4-phosphatase type II is a tumor suppressor that inhibits PI3K signaling. Cancer Cell 16: 115–125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grant DS, Kinsella JL, Fridman R, Auerbach R, Piasecki BA, Yamada Y et al. (1992). Interaction of endothelial cells with a laminin A chain peptide (SIKVAV) in vitro and induction of angiogenic behavior in vivo. J Cell Physiol 153: 614–625.

    Article  CAS  PubMed  Google Scholar 

  • Guo J, Wenk MR, Pellegrini L, Onofri F, Benfenati F, De CP . (2003). Phosphatidylinositol 4-kinase type IIalpha is responsible for the phosphatidylinositol 4-kinase activity associated with synaptic vesicles. Proc Natl Acad Sci USA 100: 3995–4000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hanahan D, Folkman J . (1996). Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86: 353–364.

    Article  CAS  PubMed  Google Scholar 

  • Heilmeyer Jr LM, Vereb Jr G, Vereb G, Kakuk A, Szivak I . (2003). Mammalian phosphatidylinositol 4-kinases. IUBMB Life 55: 59–65.

    Article  CAS  PubMed  Google Scholar 

  • Hellwig-Burgel T, Rutkowski K, Metzen E, Fandrey J, Jelkmann W . (1999). Interleukin-1beta and tumor necrosis factor-alpha stimulate DNA binding of hypoxia-inducible factor-1. Blood 94: 1561–1567.

    CAS  PubMed  Google Scholar 

  • Hsuan JJ . (1993). Oncogene regulation by growth factors. Anticancer Res 13: 2521–2532.

    CAS  PubMed  Google Scholar 

  • Huang LE, Bunn HF . (2003). Hypoxia-inducible factor and its biomedical relevance. J Biol Chem 278: 19575–19578.

    Article  CAS  PubMed  Google Scholar 

  • Jiang BH, Zheng JZ, Leung SW, Roe R, Semenza GL . (1997). Transactivation and inhibitory domains of hypoxia-inducible factor 1alpha. Modulation of transcriptional activity by oxygen tension. J Biol Chem 272: 19253–19260.

    Article  CAS  PubMed  Google Scholar 

  • Kauffmann-Zeh A, Klinger R, Kauffmann-Zeh A, Endemann G, Waterfield MD, Wetzker R et al. (1994). Regulation of human type II phosphatidylinositol kinase activity by epidermal growth factor-dependent phosphorylation and receptor association. J Biol Chem 269: 31243–31251.

    CAS  PubMed  Google Scholar 

  • Koesters R, von Knebel DM . (2003). The Wnt signaling pathway in solid childhood tumors. Cancer Lett 198: 123–138.

    Article  CAS  PubMed  Google Scholar 

  • Kubota Y, Kleinman HK, Martin GR, Lawley TJ . (1988). Role of laminin and basement membrane in the morphological differentiation of human endothelial cells into capillary-like structures. J Cell Biol 107: 1589–1598.

    Article  CAS  PubMed  Google Scholar 

  • Kung AL, Wang S, Klco JM, Kaelin WG, Livingston DM . (2000). Suppression of tumor growth through disruption of hypoxia-inducible transcription. Nat Med 6: 1335–1340.

    Article  CAS  PubMed  Google Scholar 

  • Lee JW, Bae SH, Jeong JW, Kim SH, Kim KW . (2004). Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions. Exp Mol Med 36: 1–12.

    Article  PubMed  Google Scholar 

  • Melillo G, Musso T, Sica A, Taylor LS, Cox GW, Varesio L . (1995). A hypoxia-responsive element mediates a novel pathway of activation of the inducible nitric oxide synthase promoter. J Exp Med 182: 1683–1693.

    Article  CAS  PubMed  Google Scholar 

  • Minogue S, Anderson JS, Waugh MG, dos Santos M, Corless S, Cramer R et al. (2001). Cloning of a human type ii phosphatidylinositol 4-kinase reveals a novel lipid kinase family. J Biol Chem 276: 16635–16640.

    Article  CAS  PubMed  Google Scholar 

  • Minogue S, Waugh MG, De Matteis MA, Stephens DJ, Berditchevski F, Hsuan JJ . (2006). Phosphatidylinositol 4-kinase is required for endosomal trafficking and degradation of the EGF receptor. J Cell Sci 119: 571–581.

    Article  CAS  PubMed  Google Scholar 

  • Pan W, Choi SC, Wang H, Qin Y, Volpicelli-Daley L, Swan L et al. (2008). Wnt3a-mediated formation of phosphatidylinositol 4,5-bisphosphate regulates LRP6 phosphorylation. Science 321: 1350–1353.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qin Y, Li L, Pan W, Wu D . (2009). Regulation of phosphatidylinositol kinases and metabolism by Wnt3a and Dvl2. J Biol Chem 284: 22544–22548.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roskoski Jr R . (2004). The ErbB/HER receptor protein-tyrosine kinases and cancer. Biochem Biophys Res Commun 319: 1–11.

    Article  CAS  PubMed  Google Scholar 

  • Salazar G, Zlatic S, Craige B, Peden AA, Pohl J, Faundez V . (2009). Hermansky-Pudlak syndrome protein complexes associate with phosphatidylinositol 4-kinase type II alpha in neuronal and non-neuronal cells. J Biol Chem 284: 1790–1802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scott GK, Dodson JM, Montgomery PA, Johnson RM, Sarup JC, Wong WL et al. (1991). p185HER2 signal transduction in breast cancer cells. J Biol Chem 266: 14300–14305.

    CAS  PubMed  Google Scholar 

  • Semenza GL . (2001). Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology. Trends Mol Med 7: 345–350.

    Article  CAS  PubMed  Google Scholar 

  • Semenza GL . (2002). HIF-1 and tumor progression: pathophysiology and therapeutics. Trends Mol Med 8: S62–S67.

    Article  CAS  PubMed  Google Scholar 

  • Simons JP, Al-Shawi R, Minogue S, Waugh MG, Wiedemann C, Evangelou S et al. (2009). Loss of phosphatidylinositol 4-kinase 2alpha activity causes late onset degeneration of spinal cord axons. Proc Natl Acad Sci USA 106: 11535–11539.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tan C, Cruet-Hennequart S, Troussard A, Fazli L, Costello P, Sutton K et al. (2004). Regulation of tumor angiogenesis by integrin-linked kinase (ILK). Cancer Cell 5: 79–90.

    Article  CAS  PubMed  Google Scholar 

  • Treins C, Giorgetti-Peraldi S, Murdaca J, Semenza GL, Van OE . (2002). Insulin stimulates hypoxia-inducible factor 1 through a phosphatidylinositol 3-kinase/target of rapamycin-dependent signaling pathway. J Biol Chem 277: 27975–27981.

    Article  CAS  PubMed  Google Scholar 

  • Wang YJ, Wang J, Sun HQ, Martinez M, Sun YX, Macia E et al. (2003). Phosphatidylinositol 4 phosphate regulates targeting of clathrin adaptor AP-1 complexes to the Golgi. Cell 114: 299–310.

    Article  CAS  PubMed  Google Scholar 

  • Waugh MG, Minogue S, Anderson JS, Balinger A, Blumenkrantz D, Calnan DP et al. (2003). Localization of a highly active pool of type II phosphatidylinositol 4-kinase in a p97/valosin-containing-protein-rich fraction of the endoplasmic reticulum. Biochem J 373: 57–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weber G, Shen F, Prajda N, Yeh YA, Yang H, Herenyiova M et al. (1996). Increased signal transduction activity and down-regulation in human cancer cells. Anticancer Res 16: 3271–3282.

    CAS  PubMed  Google Scholar 

  • Xu Z, Huang G, Kandror KV . (2006). Phosphatidylinositol 4-kinase type IIalpha is targeted specifically to cellugyrin-positive glucose transporter 4 vesicles. Mol Endocrinol 20: 2890–2897.

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto S, Tomita Y, Hoshida Y, Iizuka N, Monden M, Yamamoto S et al. (2004). Expression level of valosin-containing protein (p97) is correlated with progression and prognosis of non-small-cell lung carcinoma. Ann Surg Oncol 11: 697–704.

    Article  PubMed  Google Scholar 

  • Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu MM et al. (2000). Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 60: 1541–1545.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Shane Minogue and Konstantin V Kandror for gifted plasmids and Pietro De Camilli for PI4KIIα antibody, Wei Liang, Xiyun Yan and Yi Zhu for sharing materials, and Guoheng Xu and Qinwei Yin for valuable discussions. We are grateful to Nanping Wang for his great support. We also thank Junfeng Hao and Xudong Zhao for technical assistance. The work was supported by the ‘863’ National High-Technology Development Program of China (0A200202D03), the National Basic Research Program of China (2006CB911001, 2005CB522804) and the National Natural Science Foundation of China (90606020, 30770512).

Author information

Authors and Affiliations

  1. National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, PR China

    J Li, Y Lu, J Zhang, Z Qin & C Chen

  2. Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Beijing, PR China

    Y Lu, J Zhang & Z Qin

  3. Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, PR China

    H Kang

Authors
  1. J Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Z Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Z Qin or C Chen.

Ethics declarations

Competing interests

A patent has been applied by the Institute of Biophysics, CAS, CHINA (CC, JML).

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, J., Lu, Y., Zhang, J. et al. PI4KIIα is a novel regulator of tumor growth by its action on angiogenesis and HIF-1α regulation. Oncogene 29, 2550–2559 (2010). https://doi.org/10.1038/onc.2010.14

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2010.14

Keywords

This article is cited by

Search

Advanced search

Quick links