SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

T U M O R C E L L B I O L O G Y P R O G R A M
2003
Kizu, R, Okamura, K, Toriba, A, Kakishima, H,
Mizokami, A, Burnstein, KL , and Hayakawa, K.
A role of aryl hydrocarbon receptor in the
antiandrogenic effects of polycyclic aromatic hydrocarbons
in LNCaP human prostate carcinoma
cells. Archives of Toxicology 77:335-43, 2003.
Yang, E and Burnstein, KL . Vitamin D inhibits
G1 to S progression in LNCaP prostate cancer
cells through p27Kip1 stabilization and Cdk2
mislocalization to the cytoplasm. Journal of Biological
Chemistry 278:46862-68, 2003.
Chen, TC, Holick, MF, Lokeshwar, BL,
Burnstein, KL , and Schwartz, GG. Evaluation of
vitamin D analogs as therapeutic agents for prostate
cancer. Recent Results in Cancer Research
164:273-88, 2003.
Kizu, R, Okamura, K, Toriba, A, Mizokami, A,
Burnstein, KL , Klinge, CM, and Hayakawa, K.
Antiandrogenic activities of diesel exhaust particle
extracts in PC3/AR human prostate carcinoma
cells. Toxicology Sciences 76:299-309, 2003.
HIGHLIGHTS/DISCOVERIES
• Vitamin D inhibits the cell cycle by promoting
nuclear exclusion of cdk-2, which opens up new
avenues for prostate cancer therapy. Further,
regulation of cdk-2 localization represents a
new regulatory paradigm in G1 to S phase
progression.
KERMIT L. CARRAWAY, PH.D.
Professor of Cell Biology and Anatomy
DESCRIPTION OF RESEARCH
For much of the past decade, Dr. Carraway’s
primary research effort has been to examine
the role of cell surface glycoproteins in mammary
cancer, focusing on a particular glycoprotein
complex (sialomucin complex, MUC4, rat
Muc4) that his laboratory discovered about 20
years ago. This complex has both mucin- and
growth factor-containing subunits. This putative
bi-functionality can potentially contribute to two
of the major attributes of cancer cells, loss of adhesiveness,
and autonomous growth. Consistent
with both of those activities, MUC4 has been
implicated in tumor metastasis. The anti-adhesive
function of MUC4 allows it to block tumor cell
killing by lymphokine-activated killer (LAK)
cells, a mechanism that permits the MUC4-overexpressing
tumor cells to escape immune surveillance.
One of the two growth factor domains of
the transmembrane subunit of MUC4 has been
shown to act as an intramembrane ligand for the
class I tyrosine kinase growth factor receptor
ErbB2/HER2/Neu. Binding of MUC4 as a
ligand to ErbB2 potentiates tyrosine phosphorylation
of the receptor and its co-receptor ErbB3,
when the latter is stimulated with its soluble
ligand Neuregulin.
Researchers in Dr. Carraway’s laboratory are
currently investigating the effects of this receptor
modulation on downstream signaling pathways
and cellular functions. Recently, they have found
that induction of MUC4 overexpression in a
melanoma tumor cell model potentiates both primary
tumor growth and metastasis when the tumors
are injected into nude mice. The former is
correlated with a reduction in apoptosis in the
MUC4-overexpressing animals. One important
question is whether the anti-apoptotic effects of
MUC4 result from its growth factor domains or
other features of its structure. Recent results have
shown that MUC4 can regulate both the phosphorylation
and location of ErbB2 in polarized
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 69