Download Par-4 Induced Apoptosis in Cancer Cells

Par-4 Induced Apoptosis
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
hormone-dependent cancer cells, or immortalized
and primary normal cells (6). Dr. Vivek
Rangnekar and other researchers at the University
of Kentucky identified Par-4 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).
Par-4 Injection
Par-4 being injected into a fertilized mouse egg cell
(courtesy Mike Green, Markey Cancer Center, University of Kentucky)
Par-4 Structure and Location
The Par-4 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).
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).
TG-Induced Apoptosis
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 hormonedependent cancer cell has been sensitized to
TG by par-4, exposure to TG triggers
apoptosis (6).
Thapsigargin
TG-Induced Apoptosis (cont.)
Apoptosis involves chromatin condensation, cell
membrane blebbing, DNA fragmentation, and
collapse of cellular structure (6).
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).
Protein Kinase A (PKA)
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).
Leucine Zipper Domain
The leucine zipper domain must
be able to modulate the cellular
functions of other proteins (6).
The leucine zipper protein is
the part of Par-4 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).
Leucine zipper domain
Nuclear Localization
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 Par4 to enter the nucleus of cancer cells, but not
normal or immortalized cells (5). This is another
reason why Par-4 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).
Par-4 as Cancer Treatment
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).
Cost of Treatment
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/wikipedia/commons/thumb/e/e8/Leucine_zipper.png/180pxLeucine_zipper.png
Par-4:
ScienCentral News
http://www.sciencentral.com/articles/view.php3?article_id=218393034
Thapsigargin:
Wikipedia
http://upload.wikimedia.org/wikipedia/en/thumb/9/94/Thapsigargin.png/200pxThapsigargin.png
References
1. Cancer Resistance in Transgenic Mice Expressing the SAC Module of Par-4
http://cancerres.aacrjournals.org/cgi/content/abstract/67/19/9276
2. Dr. Rangnekar
http://www.mc.uky.edu/microbiology/rangnekar-pubs.asp
http://www.mc.uky.edu/microbiology/rangnekar.asp
3. Future Drugs- Expert Review of Anticancer Therapy
http://www.future-drugs.com/doi/abs/10.1586/14737140.8.1.5
4. Anti-Cancer Mouse: Science Videos
http://www.sciencentral.com/articles/view.php3?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=long&pmid=15657440
References (cont.)
6. Expression and function of the leucine zipper protein Par-4 in apoptosis
http://mcb.asm.org/cgi/content/abstract/17/7/3823?maxtoshow=&HITS=10&hits=10&RESULTFO
RMAT=&searchid=1&FIRSTINDEX=0&minscore=4000&resourcetype=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