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J Med Genet 46:497-510 doi:10.1136/jmg.2009.066944
  • Review

Apoptosis and cancer: mutations within caspase genes

  1. S Ghavami1,2,3,
  2. M Hashemi4,
  3. S R Ande5,
  4. B Yeganeh6,
  5. W Xiao5,
  6. M Eshraghi5,6,
  7. C J Bus7,
  8. K Kadkhoda8,
  9. E Wiechec9,
  10. A J Halayko1,2,3,
  11. M Los7
  1. 1
    Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada
  2. 2
    National Training Program in Allergy and Asthma, University of Manitoba, Winnipeg, Manitoba, Canada
  3. 3
    Biology of Breathing Group, Manitoba Institute of Child Health, Winnipeg, Manitoba, Canada
  4. 4
    Department of Clinical Biochemistry, and Cellular Molecular Research Centre, Zahedan University of Medical Sciences, Zahedan, Iran
  5. 5
    MICB, CancerCare Manitoba, Winnipeg, Manitoba, Canada
  6. 6
    Institute of Cardiovascular Sciences, St Boniface General Hospital Research Centre, and Department of Biochemistry & Medical Genetics, Faculty of Medicine, University of Manitoba, Winnipeg, Canada
  7. 7
    Interfaculty Institute for Biochemistry, University of Tübingen, Germany
  8. 8
    Postgraduate medical education, Faculty of Medicine, University of Manitoba and Diagnostic Services of Manitoba, Winnipeg, Manitoba, Canada
  9. 9
    Department of Human Genetics, University of Aarhus, Aarhus, Denmark
  1. Dr M Los, Interfaculty Institute of Biochemistry, University of Tübingen, Hoppe-Seyler-Str. 4/402, D-72076 Tübingen, Germany; mjelos{at}gmail.com
  • Received 6 February 2009
  • Revised 24 March 2009
  • Accepted 13 April 2009
  • Published Online First 7 June 2009

Abstract

The inactivation of programmed cell death has profound effects not only on the development but also on the overall integrity of multicellular organisms. Beside developmental abnormalities, it may lead to tumorigenesis, autoimmunity, and other serious health problems. Deregulated apoptosis may also be the leading cause of cancer therapy chemoresistance. Caspase family of cysteinyl-proteases plays the key role in the initiation and execution of programmed cell death. This review gives an overview of the role of caspases, their natural modulators like IAPs, FLIPs, and Smac/Diablo in apoptosis and upon inactivation, and also in cancer development. Besides describing the basic mechanisms governing programmed cell death, a large part of this review is dedicated to previous studies that were focused on screening tumours for mutations within caspase genes as well as their regulators. The last part of this review discusses several emerging treatments that involve modulation of caspases and their regulators. Thus, we also highlight caspase cascade modulating experimental anticancer drugs like cFLIP-antagonist CDDO-Me; cIAP1 antagonists OSU-03012 and ME-BS; and XIAP small molecule antagonists 1396–11, 1396–12, 1396–28, triptolide, AEG35156, survivin/Hsp90 antagonist shephedrin, and some of the direct activators of procaspase-3.

Footnotes

  • Funding: SG is supported by a CIHR/Canadian Lung Association/GSK Fellowship, Manitoba Institute of child Health (MICH), and by the National Training Program in Allergy and Asthma (NTPAA). AJH holds a Canada Research Chair; ME is supported by a MICH studentship, and BY is supported by CIHR, Manitoba Health Research Council (MHRC), and Institute of Cardiovascular Sciences (ICS) studentship.

  • Competing interests: None declared.