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E. Ziparo - The role of Toll Like Receptors in immune responses to infections and in inflammation associated pathologies
cer risk provides evidence for a role of TLRs in
prostate cancer. Moreover, conflicting reports have
been published claiming pro- or anti-tumoral effects
of TLR9 agonist on human prostate cancer cell lines.
Mounting evidence shows that the enhancement of
innate and adaptive immunity represents the principal
mechanism by which TLR stimulation produces
antitumour activity. However, a direct pro-apoptotic
effect of TLR agonists on TLR3 + and TLR9 +
tumour cells has been recently reported (Salaun, J
Immunol. 2006; Salaun, Clin. Cancer Res. 2007). Based
on this evidence, in order to elucidate the role of
TLRs in the etiology and pathogenesis of prostate
cancer, we used as experimental model three different
cell lines: the prostatic benign human hyperplasia
cell line BPH-1, the androgen responsive cell line
LNCaP and the androgen unresponsive PC3 cell line.
Firstly, we investigated the effect of the TLR3 agonist
poly (I:C) on the proliferative and apoptotic rates
of LNCaP and PC3. We demonstrated that poly (I:C)
elicits inhibition of proliferation associated with a
significant induction of TLR3-mediated apoptosis in
both prostate cancer cell lines. However, we found
that LNCaP cells are very sensitive to poly (I:C)induced
apoptosis, whereas PC3 cells, a more aggressive
prostate cancer cell line, shows a significant
resistance to this apoptotic stimulus. Among differently
expressed genes in two cell lines, WT p53 and
androgen receptor (AR) are expressed in LNCaP
cells, whereas PC3 cells, , are null for both p53 and
AR. The dependence of prostate tumour on AR
activity is exploited in treatment of disseminated
prostate cancers, wherein ablation of AR function
induces the regression of prostate tumours mainly
through increased apoptosis. Tumour progression is
associated with inappropriately restored AR function,
despite sustained androgen ablation and/or the
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use of AR antagonists (Hsieh, Lancet Oncol. 2007)
Since PC3 cells lack AR and p53 expression, the differences
in response to poly (I:C) between LNCaP
and PC3 cells might result from variations in the AR
and p53 status of these cells. To determine whether
these differences may account for the minor susceptibility
of PC3 cells to poly (I:C)-induced effects, we
performed apoptosis assay on PC3 cells stably transfected
with AR plasmid or transiently transfected
with p53 plasmid (PC3–p53) and treated with poly
(I:C). Our results indicate that forced expression of
AR in androgen-independent prostate cancer cell
lines confers a higher sensitivity to poly (I:C)induced
apoptosis, whereas no increment of apoptosis
was observed in PC3–p53 cells.
Finally, we identified a new IFN-B-independent
pathway that involves protein kinase C (PKC)-alpha
activation as responsible for the poly (I:C)-mediated
apoptosis in LNCaP cell line.
Selected publications
Dal Secco V, Riccioli A, Padula F, Ziparo E, Filippini
A. Mouse Sertoli cells display phenotypical and functional
traits of antigen-presenting cells in response
to interferon gamma. Biol Reprod. 2008, 78: 234-42.
Paone A, Starace D, Galli R, Padula F, De Cesaris P,
Filippini A, Ziparo E, Riccioli A. Toll like receptor 3
triggers apoptosis of human prostate cancer cells
through a PKC-alpha-dependent mechanisms.
Carcinogenesis 2008, 29:1334-42.
Starace D, Galli R, Paone A, De Cesaris P, Filippini
A, Ziparo E, Riccioli A. Toll-like receptor 3 activation
induces antiviral immune responses in mouse
Sertoli cells. Biol Reprod. 2008, 79: 766-75.