Targeting PI3-Kinases in Modulating Autophagy and Anti-cancer Therapy

Part of the Current Cancer Research book series (CUCR)


Phosphoinositide 3-kinases (hereafter referred to as PI3-kinases) are lipid kinases that phosphorylate the 3′-hydroxyl group of inositol lipids. The generated phospholipids are critical signaling molecules that recruit proteins to specific intracellular membranes leading to localized activation of these proteins. PI3-kinases regulate many cellular activities, and are closely linked to human diseases, including cancer. One molecular event regulated by PI3-kinases is autophagy, an evolutionarily conserved membrane trafficking process that degrades and recycles cellular constituents to maintain cell and tissue homeostasis. Over the past two decades, our understanding of PI3-kinases has progressed from pan-PI3-kinase inhibitor studies to isoform-specific genetic knockout and systems biology interactome analyses. Our view of autophagy has emerged from unicellular yeast vesicle trafficking to mammalian physiology and human diseases. In this chapter we summarize the major discoveries on autophagy regulation by PI3-kinases and discuss the therapeutic potentials of targeting PI3-kinases in modulating autophagy and in cancer therapy.


Autophagy PI3K Cancer therapy Chloroquine p110α p110β Vps34 


  1. Amaravadi, R. K., Lippincott-Schwartz, J., Yin, X. M., Weiss, W. A., Takebe, N., Timmer, W., et al. (2011). Principles and current strategies for targeting autophagy for cancer treatment. Clinical Cancer Research, 17, 654–666.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Auger, K. R., Serunian, L. A., Soltoff, S. P., Libby, P., & Cantley, L. C. (1989). PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells. Cell, 57, 167–175.CrossRefPubMedGoogle Scholar
  3. Blommaart, E. F., Krause, U., Schellens, J. P., Vreeling-Sindelarova, H., & Meijer, A. J. (1997). The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 inhibit autophagy in isolated rat hepatocytes. European Journal of Biochemistry, 243, 240–246.CrossRefPubMedGoogle Scholar
  4. Burgering, B. M., & Coffer, P. J. (1995). Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature, 376, 599–602.CrossRefPubMedGoogle Scholar
  5. Cantley, L. C. (2002). The phosphoinositide 3-kinase pathway. Science, 296, 1655–1657.CrossRefPubMedGoogle Scholar
  6. Christoforidis, S., Miaczynska, M., Ashman, K., Wilm, M., Zhao, L., Yip, S. C., et al. (1999). Phosphatidylinositol-3-OH kinases are Rab5 effectors. Nature Cell Biology, 1, 249–252.CrossRefPubMedGoogle Scholar
  7. Ciraolo, E., Iezzi, M., Marone, R., Marengo, S., Curcio, C., Costa, C., et al. (2008). Phosphoinositide 3-kinase p110beta activity: Key role in metabolism and mammary gland cancer but not development. Science Signaling, 1, ra3.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Dou, Z., Chattopadhyay, M., Pan, J. A., Guerriero, J. L., Jiang, Y. P., Ballou, L. M., et al. (2010). The class IA phosphatidylinositol 3-kinase p110-beta subunit is a positive regulator of autophagy. Journal of Cell Biology, 191, 827–843.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Dou, Z., Pan, J. A., Dbouk, H. A., Ballou, L. M., DeLeon, J. L., Fan, Y., et al. (2013). Class IA PI3K p110beta subunit promotes autophagy through Rab5 small GTPase in response to growth factor limitation. Molecular Cell, 50, 29–42.CrossRefPubMedPubMedCentralGoogle Scholar
  10. Dowdle, W. E., Nyfeler, B., Nagel, J., Elling, R. A., Liu, S., Triantafellow, E., et al. (2014). Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo. Nature Cell Biology, 16, 1069–1079.CrossRefPubMedGoogle Scholar
  11. Engelman, J. A., Luo, J., & Cantley, L. C. (2006). The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nature Reviews Genetics, 7, 606–619.CrossRefPubMedGoogle Scholar
  12. Fan, W., Nassiri, A., & Zhong, Q. (2011). Autophagosome targeting and membrane curvature sensing by Barkor/Atg14(L). Proceedings of the National Academy of Sciences of the United States of America, 108, 7769–7774.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Franke, T. F., Yang, S. I., Chan, T. O., Datta, K., Kazlauskas, A., Morrison, D. K., et al. (1995). The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell, 81, 727–736.CrossRefPubMedGoogle Scholar
  14. Fruman, D. A., & Rommel, C. (2014). PI3K and cancer: Lessons, challenges and opportunities. Nature Reviews Drug Discovery, 13, 140–156.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Funderburk, S. F., Wang, Q. J., & Yue, Z. (2010). The Beclin 1-VPS34 complex—at the crossroads of autophagy and beyond. Trends in Cell Biology, 20, 355–362.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Galluzzi, L., Pietrocola, F., Bravo-San Pedro, J. M., Amaravadi, R. K., Baehrecke, E. H., Cecconi, F., et al. (2015). Autophagy in malignant transformation and cancer progression. EMBO Journal, 34, 856–880.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Geering, B., Cutillas, P. R., Nock, G., Gharbi, S. I., & Vanhaesebroeck, B. (2007). Class IA phosphoinositide 3-kinases are obligate p85-p110 heterodimers. Proceedings of the National Academy of Sciences of the United States of America, 104, 7809–7814.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Gupta, S., Ramjaun, A. R., Haiko, P., Wang, Y., Warne, P. H., Nicke, B., et al. (2007). Binding of ras to phosphoinositide 3-kinase p110alpha is required for ras-driven tumorigenesis in mice. Cell, 129, 957–968.CrossRefPubMedGoogle Scholar
  19. Hamasaki, M., Furuta, N., Matsuda, A., Nezu, A., Yamamoto, A., Fujita, N., et al. (2013). Autophagosomes form at ER-mitochondria contact sites. Nature, 495, 389–393.CrossRefPubMedGoogle Scholar
  20. Hawkins, P. T., Jackson, T. R., & Stephens, L. R. (1992). Platelet-derived growth factor stimulates synthesis of PtdIns(3,4,5)P3 by activating a PtdIns(4,5)P2 3-OH kinase. Nature, 358, 157–159.CrossRefPubMedGoogle Scholar
  21. Herman, P. K., & Emr, S. D. (1990). Characterization of VPS34, a gene required for vacuolar protein sorting and vacuole segregation in Saccharomyces cerevisiae. Molecular and Cellular Biology, 10, 6742–6754.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Hiles, I. D., Otsu, M., Volinia, S., Fry, M. J., Gout, I., Dhand, R., et al. (1992). Phosphatidylinositol 3-kinase: Structure and expression of the 110 kd catalytic subunit. Cell, 70, 419–429.CrossRefPubMedGoogle Scholar
  23. Jaber, N., Dou, Z., Chen, J. S., Catanzaro, J., Jiang, Y. P., Ballou, L. M., et al. (2012). Class III PI3K Vps34 plays an essential role in autophagy and in heart and liver function. Proceedings of the National Academy of Sciences of the United States of America, 109, 2003–2008.CrossRefPubMedPubMedCentralGoogle Scholar
  24. Jia, S., Liu, Z., Zhang, S., Liu, P., Zhang, L., Lee, S. H., et al. (2008). Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis. Nature, 454, 776–779.PubMedPubMedCentralGoogle Scholar
  25. Kihara, A., Kabeya, Y., Ohsumi, Y., & Yoshimori, T. (2001a). Beclin-phosphatidylinositol 3-kinase complex functions at the trans-Golgi network. EMBO Reports, 2, 330–335.CrossRefPubMedPubMedCentralGoogle Scholar
  26. Kihara, A., Noda, T., Ishihara, N., & Ohsumi, Y. (2001b). Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae. Journal of Cell Biology, 152, 519–530.CrossRefPubMedPubMedCentralGoogle Scholar
  27. Kim, J., Kim, Y. C., Fang, C., Russell, R. C., Kim, J. H., Fan, W., et al. (2013). Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy. Cell, 152, 290–303.CrossRefPubMedPubMedCentralGoogle Scholar
  28. Kim, J., Kundu, M., Viollet, B., & Guan, K. L. (2011). AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nature Cell Biology, 13, 132–141.CrossRefPubMedPubMedCentralGoogle Scholar
  29. Laplante, M., & Sabatini, D. M. (2012). mTOR signaling in growth control and disease. Cell, 149, 274–293.CrossRefPubMedPubMedCentralGoogle Scholar
  30. Liang, C., Feng, P., Ku, B., Dotan, I., Canaani, D., Oh, B. H., et al. (2006). Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG. Nature Cell Biology, 8, 688–699.CrossRefPubMedGoogle Scholar
  31. Liang, X. H., Jackson, S., Seaman, M., Brown, K., Kempkes, B., Hibshoosh, H., et al. (1999). Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature, 402, 672–676.CrossRefPubMedGoogle Scholar
  32. Liang, C., Lee, J. S., Inn, K. S., Gack, M. U., Li, Q., Roberts, E. A., et al. (2008). Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking. Nature Cell Biology, 10, 776–787.CrossRefPubMedPubMedCentralGoogle Scholar
  33. Lin, S. Y., Li, T. Y., Liu, Q., Zhang, C., Li, X., Chen, Y., et al. (2012). GSK3-TIP60-ULK1 signaling pathway links growth factor deprivation to autophagy. Science, 336, 477–481.CrossRefPubMedGoogle Scholar
  34. Maehama, T., & Dixon, J. E. (1998). The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. Journal of Biological Chemistry, 273, 13375–13378.CrossRefPubMedGoogle Scholar
  35. Matsunaga, K., Morita, E., Saitoh, T., Akira, S., Ktistakis, N. T., Izumi, T., et al. (2010). Autophagy requires endoplasmic reticulum targeting of the PI3-kinase complex via Atg14L. Journal of Cell Biology, 190, 511–521.CrossRefPubMedPubMedCentralGoogle Scholar
  36. Matsunaga, K., Saitoh, T., Tabata, K., Omori, H., Satoh, T., Kurotori, N., et al. (2009). Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nature Cell Biology, 11, 385–396.CrossRefPubMedGoogle Scholar
  37. McAfee, Q., Zhang, Z., Samanta, A., Levi, S. M., Ma, X. H., Piao, S., et al. (2012). Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency. Proceedings of the National Academy of Sciences of the United States of America, 109, 8253–8258.CrossRefPubMedPubMedCentralGoogle Scholar
  38. Mihaylova, M. M., & Shaw, R. J. (2011). The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nature Cell Biology, 13, 1016–1023.CrossRefPubMedPubMedCentralGoogle Scholar
  39. Miller, S., Tavshanjian, B., Oleksy, A., Perisic, O., Houseman, B. T., Shokat, K. M., et al. (2010). Shaping development of autophagy inhibitors with the structure of the lipid kinase Vps34. Science, 327, 1638–1642.CrossRefPubMedPubMedCentralGoogle Scholar
  40. Myers, M. P., Pass, I., Batty, I. H., Van der Kaay, J., Stolarov, J. P., Hemmings, B. A., et al. (1998). The lipid phosphatase activity of PTEN is critical for its tumor suppressor function. Proceedings of the National Academy of Sciences of the United States of America, 95, 13513–13518.CrossRefPubMedPubMedCentralGoogle Scholar
  41. Petiot, A., Ogier-Denis, E., Blommaart, E. F., Meijer, A. J., & Codogno, P. (2000). Distinct classes of phosphatidylinositol 3′-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells. Journal of Biological Chemistry, 275, 992–998.CrossRefPubMedGoogle Scholar
  42. Rangwala, R., Leone, R., Chang, Y. C., Fecher, L. A., Schuchter, L. M., Kramer, A., et al. (2014). Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma. Autophagy, 10, 1369–1379.CrossRefPubMedPubMedCentralGoogle Scholar
  43. Ravikumar, B., Imarisio, S., Sarkar, S., O’Kane, C. J., & Rubinsztein, D. C. (2008). Rab5 modulates aggregation and toxicity of mutant huntingtin through macroautophagy in cell and fly models of Huntington disease. Journal of Cell Science, 121, 1649–1660.CrossRefPubMedPubMedCentralGoogle Scholar
  44. Ronan, B., Flamand, O., Vescovi, L., Dureuil, C., Durand, L., Fassy, F., et al. (2014). A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy. Nature Chemical Biology, 10, 1013–1019.CrossRefPubMedGoogle Scholar
  45. Rosenfeld, M. R., Ye, X., Supko, J. G., Desideri, S., Grossman, S. A., Brem, S., et al. (2014). A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme. Autophagy, 10, 1359–1368.CrossRefPubMedPubMedCentralGoogle Scholar
  46. Rostislavleva, K., Soler, N., Ohashi, Y., Zhang, L., Pardon, E., Burke, J. E., et al. (2015). Structure and flexibility of the endosomal Vps34 complex reveals the basis of its function on membranes. Science, 350, aac7365.CrossRefPubMedPubMedCentralGoogle Scholar
  47. Ruderman, N. B., Kapeller, R., White, M. F., & Cantley, L. C. (1990). Activation of phosphatidylinositol 3-kinase by insulin. Proceedings of the National Academy of Sciences of the United States of America, 87, 1411–1415.CrossRefPubMedPubMedCentralGoogle Scholar
  48. Schu, P. V., Takegawa, K., Fry, M. J., Stack, J. H., Waterfield, M. D., & Emr, S. D. (1993). Phosphatidylinositol 3-kinase encoded by yeast VPS34 gene essential for protein sorting. Science, 260, 88–91.CrossRefPubMedGoogle Scholar
  49. Stephens, L., Anderson, K., Stokoe, D., Erdjument-Bromage, H., Painter, G. F., Holmes, A. B., et al. (1998). Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B. Science, 279, 710–714.CrossRefPubMedGoogle Scholar
  50. Stephens, L. R., Hughes, K. T., & Irvine, R. F. (1991). Pathway of phosphatidylinositol(3,4,5)-trisphosphate synthesis in activated neutrophils. Nature, 351, 33–39.CrossRefPubMedGoogle Scholar
  51. Sun, Q., Fan, W., Chen, K., Ding, X., Chen, S., & Zhong, Q. (2008). Identification of Barkor as a mammalian autophagy-specific factor for Beclin 1 and class III phosphatidylinositol 3-kinase. Proceedings of the National Academy of Sciences of the United States of America, 105, 19211–19216.CrossRefPubMedPubMedCentralGoogle Scholar
  52. Traynor-Kaplan, A. E., Harris, A. L., Thompson, B. L., Taylor, P., & Sklar, L. A. (1988). An inositol tetrakisphosphate-containing phospholipid in activated neutrophils. Nature, 334, 353–356.CrossRefPubMedGoogle Scholar
  53. Vanhaesebroeck, B., Stephens, L., & Hawkins, P. (2012). PI3K signalling: The path to discovery and understanding. Nature Reviews Molecular Cell Biology, 13, 195–203.CrossRefPubMedGoogle Scholar
  54. Wang, R. C., Wei, Y., An, Z., Zou, Z., Xiao, G., Bhagat, G., et al. (2012). Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation. Science, 338, 956–959.CrossRefPubMedPubMedCentralGoogle Scholar
  55. Wei, Y., Zou, Z., Becker, N., Anderson, M., Sumpter, R., Xiao, G., et al. (2013). EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance. Cell, 154, 1269–1284.CrossRefPubMedPubMedCentralGoogle Scholar
  56. Whitman, M., Downes, C. P., Keeler, M., Keller, T., & Cantley, L. (1988). Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate. Nature, 332, 644–646.CrossRefPubMedGoogle Scholar
  57. Willinger, T., & Flavell, R. A. (2012). Canonical autophagy dependent on the class III phosphoinositide-3 kinase Vps34 is required for naive T-cell homeostasis. Proceedings of the National Academy of Sciences of the United States of America, 109, 8670–8675.CrossRefPubMedPubMedCentralGoogle Scholar
  58. Wong, K. K., Engelman, J. A., & Cantley, L. C. (2010). Targeting the PI3K signaling pathway in cancer. Current Opinion in Genetics and Development, 20, 87–90.CrossRefPubMedGoogle Scholar
  59. Wu, Y. T., Tan, H. L., Shui, G., Bauvy, C., Huang, Q., Wenk, M. R., et al. (2010). Dual role of 3-methyladenine in modulation of autophagy via different temporal patterns of inhibition on class I and III phosphoinositide 3-kinase. Journal of Biological Chemistry, 285, 10850–10861.CrossRefPubMedPubMedCentralGoogle Scholar
  60. Yuan, H. X., Russell, R. C., & Guan, K. L. (2013). Regulation of PIK3C3/VPS34 complexes by MTOR in nutrient stress-induced autophagy. Autophagy, 9, 1983–1995.CrossRefPubMedPubMedCentralGoogle Scholar
  61. Zhong, Y., Wang, Q. J., Li, X., Yan, Y., Backer, J. M., Chait, B. T., et al. (2009). Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. Nature Cell Biology, 11, 468–476.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Epigenetics Program, Department of Cell and Developmental BiologyPerelman School of Medicine, University of PennsylvaniaPhiladelphiaUSA
  2. 2.Department of Chemical BiologyErnest Mario School of Pharmacy, Rutgers UniversityPiscatawayUSA
  3. 3.Cancer Institute of New JerseyNew BrunswickUSA

Personalised recommendations