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Stress Proteins and Cancer

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									Stress Proteins & Cancer

  Presented by: Carolyn Jackson
      Advisor: Dr E.L. Myles
ALL CELLS
ALL ORGANISMS
Living in the
   World
Must cope
 with…
Stress!!!
                 Introduction
   Stresses are defined as forces that on their
    own, or in combination produce, or sustain a
    strain.

   In biology, stress is the driving force behind
    the process of adaptation and evolution.

   A unique class of proteins; heat shock
    proteins have evolved to cope with the
    potential for proteins to become unstable or
    denatured when stressed and thus act as a
    defense against protein damage.
    What are heat shock proteins
      and how do they work?
   Heat shock proteins (HSPs), also called stress
    proteins, are a group of proteins that are present
    in all cells in all life forms.

   Heat shock proteins stabilize proteins and are
    involved in the folding of denatured proteins.

   HSPs were originally identified in response to
    heat
    History Of Heat Shock Proteins
   In the early 1960s, F. Ritossa first discovered the heat shock
    (HS) response while observing the salivary cells of Drosophila
    melanogaster (Ritossa, 1962).

   It was noted that heating these cells induced puffs to form at
    various regions of the polytene chromosomes. Further analysis
    revealed that these puffs were actually areas of localized
    transcription that correlated to the increase of several families
    of proteins.

   this response was termed "heat
    shock response” because heat shock was the
    most common inducer used
 Heatshock proteins are now
 known to be induced when a cell
 undergoes various other types of
 environmental stresses like cold
 and oxygen deprivation.
    Heat shock proteins assist in the recovery
    from stress either by repairing damaged
    proteins (protein refolding) or by degrading
    them, thus restoring protein homeostasis
    and promoting cell survival.
   Many of these "stress proteins" are
    common to a variety of stresses while
    others are uniquely induced by a specific
    stress.

   Some are localized to specific organelles
    and many family members have
    counterparts, referred to as heat shock
    cognates (HSCs) that are expressed
    under normal, non-stress conditions.
                  Other Functions
                         of
                  Stress Proteins
   They also shuttle proteins from one
    compartment to another inside the cell, and
    transport old proteins to ‘garbage disposals’
    inside the cell.

   HSPs are also believed to play a role in the
    presentation of pieces of proteins (or peptides)
    on the cell surface to help the immune system
    recognize diseased cells.
   A variety of chemical agents also induce
    synthesis of some of the heat shock proteins
    in organisms

   these include: oxidizing
    agents and drugs affecting energy metabo
    lism, transition series metals, sulfhydryl re
    agents, chelating drugs, amino acid analo
    gues, certain inhibitors of transcription and
    translation, steroid hormones, glucose
    deprivation ( including treatment with 2-D-
    glucose, glucosamine, tunicamycin
    etc.), ionophores, teratogens, ethanol etc.
             Classification
 The different major heat shock proteins
  are grouped, on the basis of their
  apparent molecular sizes (in kilodaltons),
  structure, and function, into different
  families.
 Those families include:
  Hsp100, Hsp90, Hsp70, Hsp60,
  HSP40 and the small heat shock proteins
  family.
TABLE 1
Functions of Hsp families



Family                      Major functions



Hsp100   Protein disaggregation, thermotolerance
Hsp90    Regulatory interactions with signaling proteins,
         stabilization of misfolded proteins

Hsp70    Protein folding, membrane transport of proteins
Hsp60    Protein folding (limited substrates in eukaryotic
         cytoplasm)

Hsp40    Protein folding, co-chaperone for Hsp70
Small    Stabilization of misfolded proteins,
Hsp      thermotolerance, eye lens structural proteins
What do heat shock proteins
 have to do with preventing
          cancer?
      Early Research with HSPs

   First research began in the1940’s.

 Tumor cells can be weakened, or attenuated, and
  injected like a vaccine into a mouse. Afterwards, if these
  same tumor cells, at full strength, are injected into the
  mouse, the mouse will reject the tumor cells and cancer
  will not develop. However, if a mouse has not been
  vaccinated in this manner, the tumor cells will ‘take’ and
  the mouse will develop cancer.
   Early studies provided the first hint of the
    enormous diversity of cancers.


   Also showed that the ability of heat shock
    proteins to prevent cancer was highly specific:
    For example, cells from tumor X can only vaccinate against tumor X,
    and vaccination with cells from tumor X does not prevent the
    development of tumor Y.
                     Tumor used for challenge

                     A     B     C D        E
Tumor used for                                  + Tumor rejected
vaccination      A   +     -     -    -     -    - Tumor grows

                 B   -     +     -    -     -
                 C   -     -     + -        -
                 D   -     -     -    +     -
                 E   -     -     -    -     +
  What element gave Heat shock
proteins their enormous specificity?
            Dr. Pramod Srivastava
   Began a series of experiments
    about 20 years ago that initially
    showed the element responsible
    for protecting the mice was HSPs.


   Later showed that heat shock
    proteins alone could not
    specifically vaccinate against
    cancer — but they could when
    they were bound to short pieces of
    proteins called peptides.

   Went on to become the founder of
    Antigenics.

   Company received the first patent
    for the vaccine covering the use of
    HSPs for the treatment of cancer
    in 1998.
Is there a correlation between
heat shock proteins and breast
            cancer?
   Heat shock proteins (hsps) are thought to
    play important roles in the cell cycle and
    cancer progression.

   Heat shock proteins (Hsps) are induced in
    vitro by several cytotoxic drugs; in human
    breast cancer cells these proteins appear
    to be involved in anti-cancer drug
    resistance.
       Current project proposals

   To determine if heat shock proteins are
    up-regulated in breast cancer cells when
    exposed to the extracts of certain plants?
    (E. purpurea, E. pallidae)

   To determine the specific hsps whose
    concentrations will be changed using
    western blotting techniques.
                 Purple Coneflower
                      History
   Echinacea (purpurea,
    pallidae, angustifolia)

   Echinacea has a rich
    tradition of use by
    North American
    Plains Indians who
    used it medicinally to
    cure wounds,
    snakebites, and as a
    blood purifier.
         Primary uses of echinacea

   Colds, coughs and flu and other upper respiratory
    conditions
    Enlarged lymph glands, sore throat
    Urinary tract infections
    Other minor infections
    May help combat herpes and candida
    Wounds, skin regeneration and skin infections
    (external use)
    Psoriasis, eczema and inflammatory skin
    conditions (external use)
        Health Benefits of Echinacea

   Echinacea increases the "non-specific"
    activity of the immune system.
        In other words, unlike a vaccine which is
        active only against a specific disease,
        echinacea stimulates the overall activity of the
        cells responsible for fighting all kinds of
        infection. Unlike antibiotics, which are directly
        lethal to bacteria, echinacea makes our own
        immune cells more efficient in attacking
        bacteria, viruses and abnormal cells, including
        cancer cells.
               Health Benefits
   Echinacea facilitates wound healing, lessens
    symptoms of and speeds recovery from viruses.

   Anti-inflammatory effects make it useful
    externally against inflammatory skin conditions
    including psoriasis and eczema. It may also
    increase resistance to candida, bronchitis,
    herpes, and other infectious conditions.
Why is this research important?
   Breast cancer is the most common form of cancer in
    women in the United States , after skin cancer
       Both its cause and its cure remain undiscovered.
       one out of nine women will develop breast cancer in her
        lifetime –
        a risk that was one out of 14 in 1960.

   This year, 39,800 women are expected to die of
    breast cancer.
       Breast cancer is the second leading cause of cancer death for
        all women (after lung cancer), and the leading overall cause of
        cancer death in women between the ages of 20 and 59. A
        woman will die from breast cancer every 13 minutes and over 1
        million women in the United States have died of this disease
        since 1970.
                  Conclusion

   If Echinacea's effect on cancer cells can be
    confirmed by further studies, it could have a
    significant impact on the medical community's
    approach to cancer treatment.

   May prove useful in helping to design more
    effective anti-cancer drugs.

   May even be useful in developing a possible
    cure for breast cancer.
              References
 www.antigenics.com.
 http://www.biochem.arizona.edu/vierling/re
  search.html
 American Cancer Society, Cancer Facts
  and Figures 2003, January 2003.
  www.cancer.org.
 Biological Research Information Center
  (BRIC), Pohang 790-784, Korea.
 National Alliance of Breast Cancer
  Organizations
        Acknowledgements
A BIG THANK YOU TO:

 Dr. E.L. Myles
 Mrs. Yvonne Myles
 Dr. Todd Gary
 Center of Excellence

								
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