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Autophagy

 

Autophagy is a highly conserved catabolic process in which cells selectively self-digest their cytoplasmic components by forming a double-membraned vesicle around sequestered material, termed the autophagosome. Fusion with a lysosome generates an autolysosome which degrades and recycles material back to the cytoplasm. This process was first identified in yeast as a survival response to starvation and it is genetically regulated by a family of ATG genes, which have known homologues in humans.

In humans, constitutive autophagy is a necessary homeostatic process which removes damaged organelles and thus can be protective against cancer. However, when a cancer is established, autophagy takes on new roles and helps cancer cells to survive in growth limiting conditions such as low oxygen, low nutrient supply and absence of normal tissue specific survival signals. Autophagy can impact on immune recognition, dormancy, differentiation and stem cell biology.

Inducing excessive/deregulated autophagy may also be a major mechanism for killing cancer cells that have deleted normal cell death programs.  Autophagic cell death has already been reported to be induced in several cancers by chemotherapeutics. In order to improve treatment of cancer, we need to better understand how to combat the survival functions of autophagy and induce a death process in cancer cells.

Publications

Peer reviewed journals:

  1. MiR-193b promotes autophagy and non-apoptotic cell death in oesophageal cancer cells Michelle J Nyhan, Tracey R O'Donovan, Antonius W.M. Boersma, Erik A.C. Wiemer, Sharon L McKenna, BMC Cancer 2016 In press.
  2. Shereen El-Mashed, Tracey R. O’Donovan, Elaine W. Kay, Ayat R. Abdallah, Mary-Clare Cathcart, Jacintha O'Sullivan, Anthony O'Grady, John Reynolds, Seamus O’Reilly, Gerald C O'Sullivan and Sharon L. McKenna. LC3B globular structures correlate with survival in esophageal adenocarcinoma. BMC Cancer 2015, 15:582
  3. O'Donovan TR, Rajendran S, O'Reilly S, O'Sullivan GC, McKenna SL. Lithium modulates autophagy in esophageal and colorectal cancer cells and enhances the efficacy of therapeutic agents in vitro and in vivo.  PLoS One. 2015 Aug 6;10(8) PMID:26248051
  4. Jianfeng Guo, Sharon L McKenna, Michael E O’Dwyer, Mary R Cahill, and Caitriona M O’Driscoll. RNA interference for multiple myeloma therapy: targeting signal transduction pathways. Expert Opinion on Therapeutic Targets. 1-15 Online pub. on July 20, 2015.
  5. Orfali N, O'Donovan TR, Nyhan MJ, Britschgi A, Tschan MP, Cahill MR, Mongan NP, Gudas LJ, McKenna SL. Induction of autophagy is a key component of all-trans-retinoic acid-induced differentiation in leukemia cells and a potential target for pharmacologic modulation. Exp Hematol. 2015 Sep;43(9):781-793 PMID: 25986473
  6. Guo J, Cahill MR, McKenna SL, O'Driscoll CM. Biomimetic nanoparticles for siRNA delivery in the treatment of leukaemia. Biotechnol Adv. 2014 Dec;32(8):1396-1409. PMID: 25218571
  7. Nina Orfali, Sharon L McKenna, Mary R Cahill, Lorraine J Gudas. Retinoid receptor signaling and autophagy in acute promyelocytic leukemia. Experimental Cell Research, 2014 May 15;324(1):1-12.
  8. Lisa C. Crowley, Tracey R. O’Donovan, Michelle J. Nyhan, Sharon L. McKenna. Pharmacological agents with inherent anti-autophagic activity can improve the cytotoxicity of Imatinib  Oncology Reports 2013 Jun;29(6):2261-8.
  9. Baukje M Elzinga, Michelle J. Nyhan, Lisa C. Crowley, Tracey R. O’Donovan, Mary R. Cahill, Sharon L. McKenna. Induction of autophagy by Imatinib sequesters Bcr-Abl in autophagosomes and down-regulates Bcr-Abl protein. American Journal of Hematology 2013, Jun;88(6):455-62. PMID:23440701
  10. Kusio-Kobialka M, Wolanin K, Podszywalow-Bartnicka P, Sikora E, Skowronek K, McKenna SL, Ghizzoni M, Dekker FJ, Piwocka K. Increased acetylation of lysine 317/320 of p53 caused by BCR-ABL protects from cytoplasmic translocation of p53 and mitochondria-dependent apoptosis in response to DNA damage. Apoptosis. 2012 Sep;17(9):950-63 PMID: 22696202
  11. Klionsky et.al., Guidelines for the Use and Interpretation of Assays for Monitoring Autophagy. Auutophagy April 2012  8:4, 445-544.
  12. Nyhan MJ, O’Donovan TR, Elzinga B, Crowley L, O’Sullivan GC, McKenna SL. The BH3 mimetic HA14-1 enhances 5-Fluorouracil induced autophagy and Type II cell death in oesophageal cancer cells. Br J Cancer. 2012 2 Feb 14;106(4):711-8. PMID:22240779
  13. O'Donovan TR, O'Sullivan GC, McKenna SL. Induction of autophagy by drug-resistant esophageal cancer cells promotes their survival and recovery following treatment with chemotherapeutics. Autophagy. 2011 May;7(5):509-24. PMID:21325880
  14. VHL genetic alteration in CCRCC does not determine de-regulation of HIF, CAIX, hnRNP A2/B1 and osteopontin. Nyhan MJ, El Mashad SM, O'Donovan TR, Ahmad S, Collins C, Sweeney P, Rogers E, O'Sullivan GC, McKenna SL. Cell. Oncol. (Dordr). 2011 Jun;34(3):225-34.
  15. Crowley LC, Elzinga BM, O'Sullivan GC, McKenna SL. Autophagy induction by Bcr-Abl-expressing cells facilitates their recovery from a targeted or nontargeted treatment.   Am J Hematol. 2011 Jan;86(1):38-47.PMID: 21132731
  16. Nyhan MJ, El Mashad SM, O'Donovan TR, Ahmad S, Collins C, Sweeney P, Rogers E, O'Sullivan GC, McKenna SL. VHL genetic alteration in CCRCC does not determine de-regulation of HIF, CAIX, hnRNP A2/B1 and osteopontin. Anal Cell Pathol (Amst). 2010 Jan 1;33(3):121-32.PMID: 20978319
  17. Wolanin K, Magalska A, Kusio-Kobialka M, Podszywalow-Bartnicka P, Vejda S, McKenna SL, Mosieniak G, Sikora E, Piwocka K. Expression of oncogenic kinase Bcr-Abl impairs mitotic checkpoint and promotes aberrant divisions and resistance to microtubule-targeting agents. Mol Cancer Ther. 2010 May;9(5):1328-38. Epub 2010 May 4 PMID: 20442314
  18. O’Sullivan-Coyne Geraldine, O’Sullivan Gerald C., Piwocka Katarzyna, McKenna S. L. Curcumin induces apoptosis-independent death in esophageal cancer cells. British Journal of Cancer 2009 Nov 3;101(9):1585-95. Epub 2009 Oct 6.PMID: 19809435
  19. Nyhan MJ, O'Sullivan GC, McKenna SL. Role of the VHL (von Hippel-Lindau) gene in renal cancer: a multifunctional tumour suppressor. Biochem Soc Trans. 2008 Jun;36(Pt 3):472-8. PMID: 18481984
  20. B. Kiely, R.T. O’Donovan S.L. McKenna, G. C. O’Sullivan. beta-Catenin transcriptional activity is inhibited downstream of nuclear localisation and is not influenced by IGF signalling in oesophageal cancer cells.  Int J Cancer.  2007 Nov 1;121(9):1903-9. PMID: 17631645
  21. Deasy BM, O'Sullivan-Coyne G, O'Donovan TR, McKenna SL*, O'Sullivan GC*. *Joint senior authors Cyclooxygenase-2 inhibitors demonstrate anti-proliferative effects in oesophageal cancer cells by prostaglandin E(2)-independent mechanisms. Cancer Lett. 2007 Oct 28;256(2):246-58.  PMID: 17707579
  22. M. Walsh, M.Tangney, J.O. Larkin, D.M. Soden, SL. McKenna, R Darcy, G.C. O’Sullivan and C.M. O’Driscoll. Evaluation of Cellular Uptake and Gene Transfer Efficiency of Pegylated Poly-L-Lysine Compacted DNA – Implications for Cancer Gene Therapy. Molecular Pharmaceutics. 2006 Nov-Dec;3(6):644-53.
  23. C. Collins, M.Tangney, J. Larkin, G.Casey, J.Cashman, D.Soden, S.Vejda, S. McKenna, B. Kiely, J. Barrett, S. Aarons G.C. O’Sullivan. (2006) Local gene therapy of solid tumors with GM-CSF and B7-1 eradicates both treated and distal tumors. Cancer Gene Ther. 2006 Dec;13(12):1061-71
  24. Kamila Wolanin, Adriana Magalska, Grażyna Mosieniak, Sharon McKenna, Susanne Vejda, Ewa Sikora and Katarzyna Piwocka. (2006) Curcumin affects components of the chromosomal passenger complex and induces mitotic catastrophe in apoptosis resistant Bcr-Abl expressing cells. Molecular Cancer Research 2006 Jul;4(7):457-69. PMID: 16849521.
  25. K. Piwocka, S. Vejda, T.G. Cotter, G.C. O’Sullivan, and SL McKenna.  Bcr-Abl reduces endoplasmic reticulum (ER) releasable calcium levels by a Bcl-2 independent mechanism and inhibits calcium dependent apoptotic signalling. Blood. 2006 May 15;107(10):4003-10. Epub 2006 Feb 9. PMID: 16469868
  26. Vejda S Piwocka K, McKenna SL*, Cotter TG*. Autocrine secretion of osteopontin results in degradation of I-kappaB in Bcr-Abl-expressing cells. Br. J. Haematol. 2005 Mar;128(5):711-21. *Joint senior authors  PMID: 15725094
  27. Keeshan K, Cotter TG, and McKenna SL. Bcr-Abl upregulates cytosolic p21WAF1/CIP1 by a phosphoinositide-3-kinase (PI3K) independent pathway. British Journal of Haematology. Oct. 123: 34-44 2003.
  28. Keeshan K, Cotter TG, McKenna SL. High Bcr-Abl expression prevents the translocation of Bax and Bad to the mitochondrion. Leukemia  2002 Sep;16(9):1725-34
  29. Keeshan K, Mills KI, Cotter TG, McKenna SL. Elevated Bcr-Abl expression levels are sufficient for a haematopoietic cell line to acquire a drug resistant phenotype.  Leukemia 2001; 15:1823-1833.
  30. O’Gorman DM, McKenna SL, McGahon AJ, Cotter TG. Inhibition of PI3-kinase sensitises HL60 human leukaemia cells to both chemotherapeutic drug and Fas-induced apoptosis. Leukaemia Research. 2001;25(9):801-11
  31. Di Bacco A, K.Keeshan, McKenna SL, Cotter TG (2000). Molecular abnormalities in Chronic Myeloid Leukaemia (CML): Deregulation of growth and apoptosis. The Oncologist. 5:(5)405-415.
  32. Parrado A, Noguere ME, Delmer A, McKenna S, Davies J, Le Gall, Bentley P, Whittaker JA, Sigaux F, Chomienne C, Padua RA. (2000). Deregulated expression of promyelocytic leukemia zinc finger protein in B-cell chronic lymphocytic leukemias does not affect cyclin A expression. Hematol J. 1(1):15-27.
  33. O’Gorman DM, McKenna SL, McGahon AJ, Knox KA, Cotter TG. (2000). Sensitisation of HL60 human leukaemic cells to cytotoxic drug-induced apoptosis by inhibition of PI-3-kinase survival signals. Leukaemia.14: 602-611
  34. Costa-Pereira AP, McKenna SL, Cotter TG. (2000). Activation of SAPK/JNK by camptothecin sensitises androgen-independent prostate cancer cells to Fas-induced apoptosis. Br. J. Cancer.82(11): 1827-34.
  35. McKenna SL, and Cotter TG. (2000). Inhibition of caspase activity delays apoptosis in a transfected NS/0 myeloma cell line. Biotechnology and Bioengineering. 67: 165-176
  36. Parrado A, Noguera ME, Delmer A, McKenna S, Davies J, Le Gall I, Bentley P, Whittaker JA, Sigaux F, Chomienne C, Padua RA. (2000) Deregulated expression of promyelocytic leukemia zinc finger protein in B-cell chronic lymphocytic leukemias does not affect cyclin A expression. Hematol J. 1(1):15-27. PMID: 11920165
  37. Parrado A, West R, Jordan D, Bastard C, McKenna S, Whittaker JA, Bently P, White D, Chomienne C Padua RA. (1999). Alterations of the retinoic acid receptor alpha (RAR alpha) gene in myeloid and lymphoid malignancies. Br. J. Haematol. 104(4): 738-741
  38. McKenna SL, Hoy T, Jackson H, Holmes, JA, Whittaker JA, Padua RA. (1998). Flow cytometric apoptosis assays indicate different types of endonuclease activity in haematopoietic cells and suggest a cautionary approach to their quantitative use. Cytometry 31: 130-136.
  39. McKenna SL, McGowan AJ, Cotter TG. Molecular mechanisms of programmed cell death. (1998). Advances in Biochemical Engineering and Biotechnology, 62: 1-31.
  40. McKenna SL and Cotter TG. Functional aspects of apoptosis in hematopoiesis and consequences of failure (1997) Advances in Cancer Research 71: 121-164.
  41. McKenna SL, Padua RA. Multi-drug resistance in Leukaemia (1997). British Journal of Haematology 96: 659-674.
  42. McKenna SL, West RR, Whittaker JA, Padua RA, Holmes JA. (1994). Topoisomerase II alpha expression in acute myeloid leukaemia and its relationship to clinical outcome. Leukemia 8: 1498-1502.
  43. McKenna SL, Whittaker JA, Padua RA, Holmes JA. (1993). Topoisomerase II expression in normal haemopoietic cells and chronic lymphocytic leukaemia: Drug sensitivity or resistance? Leukemia 7: 1119-1203.
  44. Casaregola S, Chen M, Bouquin N, Norris V, Jacq A, Goldberg M, Margarson S, Tempete M, McKenna SL, Sweetman H, Bernard S, McGurk G, Seror S, Holland IB. (1991). Analysis of a myosin-like protein and the role of calcium in the E.Coli cell cycle. Res. Microbiol. 142: 201-207.

Book Chapters:

  1. Carmody RJ, Cotter TG and McKenna SL. (2000) Programmed Cell Death. In: Encyclopedia of Cell Technology Wiley (RE Spier) Vol 2: pp1059-1068.
  2. Carmody RJ, Costa-Pereira AP, McKenna SL, Cotter TG. (2000). Detection of Molecular Events During Apoptosis by Flow Cytometry. Methods in Molecular Medicine, Vol 38: Ageing Methods and Protocols. (Ed. Barnett YA and Barnett CR) Humana Press Inc., Totowa, NJ. USA. pp 71-83
  3. McKenna SL, Carmody RJ and Cotter TG. (1999). The regulation of apoptosis in animal cells. (Ed. Al-Rubeai, M). Kluwer Academic Publishers. Cell Engineering, Volume I. pp122-161
  4. McKenna SL and Cotter TG. Apoptosis in Leukaemia. (1997). In Apoptosis in Cancer (Ed. S. Martin) Karger Landes Systems. pp192-221.
  5. Invited review Lancet Oncology: Volume 7, Issue 12, Page 979, December 2006. S.L.McKenna. Cancer Biotherapy: An Introductory guide. Edited by Annie Young, Lewis Rowett, David Kerr. ISBN 0-19-856631-X