4
to the nucleus where it recognizes promoter regions containing androgen responsive elements.
Upon recruiting several Co-regulators (Co-Reg) and the general transcription apparatus (GTA),
it induces the transcription of pro-proliferative and pro-survival genes, as well as the biomarker
prostate specific antigen (PSA).
Previous research
19,20
has found that a mutated AR is constitutively active as a transcription factor
in LNCaP, thereby perpetually promoting the above traits. This
makes LNCaP cells highly
cancerous. As mentioned above, ca27 down-regulates the expression of the AR in LNCaP cells
(Figure 3). This leads to growth inhibition and cell death
20
. ca27 features α-β-unsaturated carbon
bonds (commonly referred to as Michael acceptors) and aromatic rings as well as ortho- positioned
hydroxyl (OH) groups on the aromatic rings. Structurally diverse analogs of ca27 (see below) also
show the ability to down-regulate the expression of the AR, but with different efficiencies.
Figure 3:
The diarylpentanoid ca27 down-regulates the expression of the mutated AR in LNCaP
human prostate cancer cells at low micromolecular concentrations. Protein expression is shown
by Western blot and quantification normalized to the housekeeping gene β-actin
20
.
The different analogs of ca27 under investigation are all diarylpentanoids, however, they differ in
regard to their hydroxyl group positioning or lack of hydroxyl groups on the aryl rings. Other
5
analogs differ in the presence or absence of the α-β-unsaturated carbon bonds (Michael acceptors)
on the carbon chain. Some of the ca27 analogs under investigation are shown in Figure 4.
While the Michael acceptors and the hydroxyl groups are hypothesized to be essential to the anti-
AR expression effectiveness of ca27, its exact mechanism(s) of action remain unknown. However,
it is not inconceivable that ca27 and its analogs physically interact with the AR, thereby inducing
Figure 4:
The diarylpentanoid ca27 and its structural analogs CA58 (meta-positioned hydroxyl
[OH] groups), CA51 (para-positioned OH groups), ca27 MA- (lacking the Michael acceptors),
and ca27 OH- (lacking the OH groups). Right bottom: The natural product curcumin with its
functional groups.
6
its down regulation. The present research project explored this possibility, as outlined further in
the hypothesis (see below).
Dostları ilə paylaş: