Protease, EMT, and Cancer

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Protease, EMT, and Cancer
Cancer Biology Pathway 2006
James Hsieh, M.D. Ph.D Molecular Oncology
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Hallmarks of Cancer
Cell, v100, p57-70
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Protease

• Regulate biological processes through hydrolysing
  peptide bonds
• eg. activation or inactivation of proteases,
  other enzymes, hormone, growth factors

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Protease regulates multiple essential biological
processes and pathways

• Food consumption
• Blot clotting
• Tissue remodeling
• Ovulation, fertilization
• Angiogenesis
• Cell migration
• Cell cycle
• Apoptosis
• Neuronal outgrowth
• Notch Signaling
• SREBP signaling
• Hedgehog signaling

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Protease function underlies many human
pathological processes

• Bleeding disorder
• Cancer
• Arthritis
• Neurodegerative diseases
• Cardiovascular disease

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565 proteins comprising 1.7 human genome Only
second to ubiquitin ligase family Larger than
kinase family (465)
Cancer Reviews Genetics V4, p544
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Cancer Reviews Genetics V4, p544
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Proteases represent 5-10 of potential drug
targets
Science 2000 v287, p1960
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Proteases as drug targets

• Protease itself tPA for acute myocardial
  infarction, coagulation factors (proenzyme)
• Protease inhibitor ACE inhibitors for
  hypertension
• Proteasome inhibitor (velcade) for multiple
  myeloma

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Proteases and Cancer

• Cell death Caspase
• Metastasis ECM degradation involves uPA,
  Cathepsin, Matrix Metalloproteinases (MMPs) etc
• Markers uPA/PAI associates with high incidence
  of metastasis and poor outcome in breast cancer
  patients

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Science 2002, v295, p2387
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Matrix Metalloproteinases

• Need Zinc Ion for action
• 23 MMPs
• Only 3 were shown to be good anti-tumor targets
• MMP1, 7, 8

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• Target
• A molecule that unambiguously contributes to
  disease initiation or progression. When its
  activity is downmodulated by a drug, the normal
  state of the cell and tissue is restored. In
  cancer, such drugs might also specifically kill a
  pathologically altered and undesirable cell or
  slow disease progression.
• Anti-target
• A molecule with essential roles in normal cell
  and tissue function. Downmodulation of an
  anti-target results in clinically unacceptable
  side effects, initiation of disease, or
  deleterious alterations in disease progression.
  This results in shorter onset time of the
  disease, increased disease burden, poorer patient
  outcome or decreased survival time.
• Counter-target
• A protein that is homologous with a target but
  has no significant role in the disease. When
  modulated by a drug, counter-targets have the
  potential for undesirable altered functions or
  side effects.

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Overall et al. Nature Reviews Cancer 6, 227239
(March 2006) doi10.1038/nrc1821
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HGF/SF cMet Pathway
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