Advertisement

Targeting Deubiquitinating Enzymes and Autophagy in Cancer

  • Ashley MooneyhamEmail author
  • Martina Bazzaro
Protocol
First Online:
Part of the Methods in Molecular Biology book series (MIMB, volume 1513)

Abstract

Maintenance of proper cellular homeostasis requires constant surveillance and precise regulation of intracellular protein content. Protein monitoring and degradation is performed by two distinct pathways in a cell: the autophage–lysosome pathway and the ubiquitin–proteasome pathway. Protein degradation pathways are frequently dysregulated in multiple cancer types and can be both tumor suppressive and tumor promoting. This knowledge has presented the ubiquitin proteasome system (UPS) and autophagy as attractive cancer therapeutic targets. Deubiquitinating enzymes of the UPS have garnered recent attention in the field of cancer therapeutics due to their frequent dysregulation in multiple cancer types. The content of this chapter discusses reasoning behind and advances toward targeting autophagy and the deubiquitinating enzymes of the UPS in cancer therapy, as well as the compelling evidence suggesting that simultaneous targeting of these protein degradation systems may deliver the most effective, synergistic strategy to kill cancer cells.

Key words

Deubiquitinating enzymes Autophagy Cancer Small molecule inhibitors Ubiquitin–proteasome system 
This is a preview of subscription content, log in to check access.

References

  1. 1.
    Goldberg AL (2003) Protein degradation and protection against misfolded or damaged proteins. Nature 426:895–899CrossRefPubMedGoogle Scholar
  2. 2.
    Amm I, Sommer T, Wolf DH (2014) Protein quality control and elimination of protein waste: the role of the ubiquitin-proteasome system. Biochim Biophys Acta 1843:182–196CrossRefPubMedGoogle Scholar
  3. 3.
    Levine B (2007) Cell biology: autophagy and cancer. Nature 446:745–747CrossRefPubMedGoogle Scholar
  4. 4.
    Hoeller D, Dikic I (2009) Targeting the ubiquitin system in cancer therapy. Nature 458:438–444CrossRefPubMedGoogle Scholar
  5. 5.
    Yang ZJ, Chee CE, Huang S, Sinicrope FA (2011) The role of autophagy in cancer: therapeutic implications. Mol Cancer Ther 10:1533–1541CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Frezza M, Schmitt S, Dou QP (2011) Targeting the ubiquitin-proteasome pathway: an emerging concept in cancer therapy. Curr Top Med Chem 11:2888–2905CrossRefPubMedGoogle Scholar
  7. 7.
    Boya P, Reggiori F, Codogno P (2013) Emerging regulation and functions of autophagy. Nat Cell Biol 15:713–720CrossRefPubMedGoogle Scholar
  8. 8.
    Thorburn A, Thamm DH, Gustafson DL (2014) Autophagy and cancer therapy. Mol Pharmacol 85:830–838CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Mizushima N (2007) Autophagy: process and function. Genes Dev 21:2861–2873CrossRefPubMedGoogle Scholar
  10. 10.
    Lin Z, Bazzaro M, Wang MC et al (2009) Combination of proteasome and HDAC inhibitors for uterine cervical cancer treatment. Clin Cancer Res 15:570–577CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Bazzaro M, Lin Z, Santillan A et al (2008) Ubiquitin proteasome system stress underlies synergistic killing of ovarian cancer cells by bortezomib and a novel HDAC6 inhibitor. Clin Cancer Res 14:7340–7347CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Yang Z, Klionsky DJ (2010) Eaten alive: a history of macroautophagy. Nat Cell Biol 12:814–822CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Liang XH, Jackson S, Seaman M et al (1999) Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402:672–676CrossRefPubMedGoogle Scholar
  14. 14.
    Mathew R, Karantza-Wadsworth V, White E (2007) Role of autophagy in cancer. Nat Rev Cancer 7:961–967CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Kung CP, Budina A, Balaburski G et al (2011) Autophagy in tumor suppression and cancer therapy. Crit Rev Eukaryot Gene Expr 21:71–100CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Guo JY, Xia B, White E (2013) Autophagy-mediated tumor promotion. Cell 155:1216–1219CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Dolfi SC, Chan LL, Qiu J et al (2013) The metabolic demands of cancer cells are coupled to their size and protein synthesis rates. Cancer Metab 1:20CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Kim SE, Park HJ, Jeong HK et al (2015) Autophagy sustains the survival of human pancreatic cancer PANC-1 cells under extreme nutrient deprivation conditions. Biochem Biophys Res Commun 463:205–210CrossRefPubMedGoogle Scholar
  19. 19.
    Zhi X, Zhong Q (2015) Autophagy in cancer. F1000Prime Rep 7:18CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Zhang Y, Liao Z, Zhang LJ, Xiao HT (2015) The utility of chloroquine in cancer therapy. Curr Med Res Opin 31:1009–1013CrossRefPubMedGoogle Scholar
  21. 21.
    Lee JY, Koga H, Kawaguchi Y et al (2010) HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy. EMBO J 29:969–980CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Nagelkerke A, Bussink J, Geurts-Moespot A et al (2015) Therapeutic targeting of autophagy in cancer. Part II: Pharmacological modulation of treatment-induced autophagy. Semin Cancer Biol 31:99–105CrossRefPubMedGoogle Scholar
  23. 23.
    Ozpolat B, Benbrook DM (2015) Targeting autophagy in cancer management—strategies and developments. Cancer Manag Res 7:291–299CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Johnson DE (2015) The ubiquitin-proteasome system: opportunities for therapeutic intervention in solid tumors. Endocr Relat Cancer 22:T1–T17CrossRefPubMedGoogle Scholar
  25. 25.
    Rajkumar SV, Richardson PG, Hideshima T, Anderson KC (2005) Proteasome inhibition as a novel therapeutic target in human cancer. J Clin Oncol 23:630–639CrossRefPubMedGoogle Scholar
  26. 26.
    Chen D, Frezza M, Schmitt S et al (2011) Bortezomib as the first proteasome inhibitor anticancer drug: current status and future perspectives. Curr Cancer Drug Targets 11:239–253CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Frankland-Searby S, Bhaumik SR (2012) The 26S proteasome complex: an attractive target for cancer therapy. Biochim Biophys Acta 1825:64–76PubMedGoogle Scholar
  28. 28.
    Kane RC, Bross PF, Farrell AT, Pazdur R (2003) Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy. Oncologist 8:508–513CrossRefPubMedGoogle Scholar
  29. 29.
    Dick LR, Fleming PE (2010) Building on bortezomib: second-generation proteasome inhibitors as anti-cancer therapy. Drug Discov Today 15:243–249CrossRefPubMedGoogle Scholar
  30. 30.
    Papadopoulos KP, Burris HA 3rd, Gordon M et al (2013) A phase I/II study of carfilzomib 2-10-min infusion in patients with advanced solid tumors. Cancer Chemother Pharmacol 72:861–868CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Dou QP, Zonder JA (2014) Overview of proteasome inhibitor-based anti-cancer therapies: perspective on bortezomib and second generation proteasome inhibitors versus future generation inhibitors of ubiquitin-proteasome system. Curr Cancer Drug Targets 14:517–536CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Hussain S, Zhang Y, Galardy PJ (2009) DUBs and cancer: the role of deubiquitinating enzymes as oncogenes, non-oncogenes and tumor suppressors. Cell Cycle 8:1688–1697CrossRefPubMedGoogle Scholar
  33. 33.
    Lim KH, Baek KH (2013) Deubiquitinating enzymes as therapeutic targets in cancer. Curr Pharm Des 19:4039–4052CrossRefPubMedGoogle Scholar
  34. 34.
    Reyes-Turcu FE, Ventii KH, Wilkinson KD (2009) Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes. Annu Rev Biochem 78:363–397CrossRefPubMedGoogle Scholar
  35. 35.
    Amerik AY, Hochstrasser M (2004) Mechanism and function of deubiquitinating enzymes. Biochim Biophys Acta 1695:189–207CrossRefPubMedGoogle Scholar
  36. 36.
    Ndubaku C, Tsui V (2015) Inhibiting the deubiquitinating enzymes (DUBs). J Med Chem 58:1581–1595CrossRefPubMedGoogle Scholar
  37. 37.
    Yang JM (2007) Emerging roles of deubiquitinating enzymes in human cancer. Acta Pharmacol Sin 28:1325–1330CrossRefPubMedGoogle Scholar
  38. 38.
    McClurg UL, Robson CN (2015) Deubiquitinating enzymes as oncotargets. Oncotarget 6:9657–9668CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    D'Arcy P, Wang X, Linder S (2015) Deubiquitinase inhibition as a cancer therapeutic strategy. Pharmacol Ther 147:32–54CrossRefPubMedGoogle Scholar
  40. 40.
    Anchoori RK, Karanam B, Peng S et al (2013) A bis-benzylidine piperidone targeting proteasome ubiquitin receptor RPN13/ADRM1 as a therapy for cancer. Cancer Cell 24:791–805CrossRefPubMedGoogle Scholar
  41. 41.
    Kapuria V, Peterson LF, Fang D et al (2010) Deubiquitinase inhibition by small-molecule WP1130 triggers aggresome formation and tumor cell apoptosis. Cancer Res 70:9265–9276CrossRefPubMedGoogle Scholar
  42. 42.
    Donato NJ, Talpaz M, Peterson L et al (2015) Deubiquitinase inhibitors and methods for use of the same. Google Patents Publication number WO2015054555 A1Google Scholar
  43. 43.
    Tian Z, D'Arcy P, Wang X et al (2014) A novel small molecule inhibitor of deubiquitylating enzyme USP14 and UCHL5 induces apoptosis in multiple myeloma and overcomes bortezomib resistance. Blood 123:706–716CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Wang X, D'Arcy P, Caulfield TR et al (2015) Synthesis and evaluation of derivatives of the proteasome deubiquitinase inhibitor b-AP15. Chem Biol Drug Des 86:1036–1048CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Coughlin K, Anchoori R, Iizuka Y et al (2014) Small-molecule RA-9 inhibits proteasome-associated DUBs and ovarian cancer in vitro and in vivo via exacerbating unfolded protein responses. Clin Cancer Res 20:3174–3186CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Kushwaha D, O'Leary C, Cron KR et al (2015) USP9X inhibition promotes radiation-induced apoptosis in non-small cell lung cancer cells expressing mid-to-high MCL1. Cancer Biol Ther 16:392–401CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Korolchuk VI, Menzies FM, Rubinsztein DC (2010) Mechanisms of cross-talk between the ubiquitin-proteasome and autophagy-lysosome systems. FEBS Lett 584:1393–1398CrossRefPubMedGoogle Scholar
  48. 48.
    Vogel RI, Coughlin K, Scotti A et al (2015) Simultaneous inhibition of deubiquitinating enzymes (DUBs) and autophagy synergistically kills breast cancer cells. Oncotarget 6:4159–4170CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Masonic Cancer Center and Department of Obstetrics, Gynecology and Women’s HealthUniversity of Minnesota Twin CitiesMinneapolisUSA

Personalised recommendations

Cite protocol

Buy options