Download Par-4 as a Cancer Treatment

Par-4 Induced Apoptosis
By Ashley Feng and Lilly Holman
Par-4
Overexpression of the prostate apoptosis response
gene-4 (Par-4) causes apoptosis in hormoneindependent cancer cells, but does not affect hormonedependent cancer cells, or immortalized and primary
normal cells (6). Dr. Vivek Rangnekar and other
researchers at the University of Kentucky identified Par4 in 1993 and have found that mice that overexpress the
Par-4 gene are resistant to cancer (2). Par-4 could
potentially be used to treat cancer, since it kills only
cancer cells and has no known side effects (3). The Par4 gene maps to human chromosome 12q21 (5). This
region is often destroyed in pancreatic and gastric
cancer cells (5). Par-4 is induced by apoptic signals
which are not necrotic, and do not affect growth (6). The
protein expressed by this gene is proapoptic and has a
leucine zipper domain at its carboxy terminus (5).
Mechanism
The ability of Par-4 to cause apoptosis
depends upon overexpression (6),
phosphorylation of T155 on Par-4 by Protein
Kinase A (PKA) (5), the leucine zipper domain
on Par-4, the presence of thapsigargin (TG)
(6,9), and nuclear localization signal domains
(5,6). When any of these factors was mutated
or otherwise nullified, Par-4 could not trigger
apoptosis (5,6).
TG-Induced Apoptosis
Nuclear Localization
Overexpression of Par-4 does not cause
apoptosis on its own. Par-4 only sensitizes cancer
cells to thapsigargin (6). Apoptosis can be induced
in androgen-dependent cells by upregulation of
intracellular calcium with calcium ionophores or
with thapsigargin (TG), which activates the
capacitative calcium channel (6,7). After a
hormone-dependent cancer cell has been
sensitized to TG by par-4, exposure to TG triggers
apoptosis (6). Apoptosis involves chromatin
condensation, cell membrane blebbing, DNA
fragmentation, and collapse of cellular structure (6).
Nuclear localization signal (NLS) domains are
also necessary for Par-4 to function (5). In
experiments, Par-4 without a NSL domain could not
induce apoptosis (5). NLS domains allow Par-4 to
enter the nucleus of cancer cells, but not normal or
immortalized cells (5). This is another reason why Par4 does not affect normal cells. The SAC domain
mutant of Par-4 can cause apoptosis in an even wider
range of cancer cells, but still does not affect normal
or immortalized cells (5).
Thapsigargin
Par-4 as a Cancer Treatment
Par-4 being injected into a fertilized
mouse egg cell
Apoptosis
Protein Kinase A (PKA)
Protein Kinase A (PKA) phosphorylates and activates the
selective for apoptosis induction in cancer cells (SAC) domain
(5). The SAC domain is called that because it does not trigger
apoptosis in normal or immortal cells (1). Par-4 does not affect
normal cells because it must be phosphorylated by PKA in
order to trigger apoptosis (5). PKA 1 is overexpressed by
primary tumors and cancer cells (5). Production of PKA 1 is
related to transformation by growth factors in cancer cells, and
high levels of PKA activate Par-4, which leads to high levels of
apoptosis only in cancer cells (5).
Overexpression
Normal levels of Par-4 do not cause
apoptosis; this is easily proven because
basal levels of Par-4 in animals with
prostate cancer do not cause apoptosis (6).
Ectopic overexpression of Par-4 facilitates
TG-inducible apoptosis in prostate cancer
and melanoma cells (6).
Researchers believe Par-4 would be an ideal cancer
treatment because it causes apoptosis in only cancer cells
(3). Par-4 has no harmful effects on normal cells, and no
known side effects, unlike current treatments such as
chemotherapy (1). Mice injected with the Par-4 gene
experienced significant shrinking of tumors and even had a
longer lifespan than normal mice with prostate cancer (4).
Par-4 treatment has not been tested on humans, but
researchers believe Par-4 could be administered to human
patients through bone marrow transplants (3). The potential
cost of this treatment is yet unknown, since there is a
significant amount of research to be done until Par-4
treatment can become available to cancer patients.
Image References
Apoptosis: Technische Universiteit
Eindhoven
http://www.bmt.tue.nl/research/unit
%20descriptions/apoptosis.GIF
Leucine Zipper Domain:
Wikipedia
http://upload.wikimedia.org/wikipedi
a/commons/thumb/e/e8/Leucine_zip
per.png/180px-Leucine_zipper.png
Leucine Zipper Domain
Par-4:
ScienCentral News
http://www.sciencentral.com/articles/
view.php3?article_id=218393034
The leucine zipper domain must
be able to modulate the cellular
functions of other proteins (6). The
leucine zipper protein is the part of Par4 that the protein uses to bond to the
zinc finger domain of Wilms’ tumor
protein WT1 (8), and it is essential for
Par-4 to induce apoptosis (6).
Thapsigargin
Wikipedia
http://upload.wikimedia.org/wikipedi
a/en/thumb/9/94/Thapsigargin.png/2
00px-Thapsigargin.png
Leucine zipper domain
References
1. Cancer Resistance in Transgenic Mice Expressing
the SAC Module of Par
http://cancerres.aacrjournals.org/cgi/content/abstract
/67/19/9276
2. Dr. Rangnekar
http://www.mc.uky.edu/microbiology/rangnekarpubs.asp
http://www.mc.uky.edu/microbiology/rangnekar.asp
3. Future Drugs- Expert Review of Anticancer
Therapy
http://www.futuredrugs.com/doi/abs/10.1586/14737140.8.1.5
4. Anti-Cancer Mouse: Science Videos
http://www.sciencentral.com/articles/view.ph
p3?article_id=218393034
5. Phosphorylation of Par-4 by Protein Kinase A Is
Critical for Apoptosis
http://mcb.asm.org/cgi/content/full/25/3/1146?view=lo
ng&pmid=15657440
6. Expression and function of the leucine zipper
protein Par-4 in apoptosis
http://mcb.asm.org/cgi/content/abstract/17/7/3823?m
axtoshow=&HITS=10&hits=10&RESULTFORMAT=&
searchid=1&FIRSTINDEX=0&minscore=4000&resou
rcetype=HWCIT
7. Thapsigargin, a Tumor Promoter, Discharges
Intracellular Ca2+ Stores by Specific Inhibition of the
Endoplasmic Reticulum Ca2+-ATPase
http://www.pnas.org/cgi/content/abstract/87/7/2466
8. Par-4 transcriptionally regulates Bcl-2 through a
WT1-binding site on the bcl-2 promoter
http://www.ncbi.nlm.nih.gov/pubmed/12644474
9. Role of EGR-1 in Thapsigargin-Inducible
Apoptosis in the Melanoma Cell Line A375-C6
http://mcb.asm.org/cgi/content/abstract/15/11/6262