Survivin, a member of inhibitor of apoptosis family, is associated with both
prostate cancer progression and drug resistance. Therefore, we hypothesized that
survivin may play a potentially important role in
hormone-refractory
prostate cancer (HRPC) and bone metastatic disease; thus, targeting of
survivin signaling could enhance therapeutic efficacy in
prostate cancer.
3,3'-Diindolylmethane (DIM) has been known to have
cancer chemoprevention activity. However, no information is available regarding the down-regulation of
survivin by DIM, which could result in the chemosensitization of HRPC cells to
Taxotere-induced killing. We investigated the effect of DIM alone or in combination with
Taxotere using LNCaP and C4-2B
prostate cancer cells. We observed that DIM enhanced
Taxotere-induced apoptotic death in both cell lines. These enhancing effects were related to a decrease in
survivin expression as well as
androgen receptor and
nuclear factor-kappaB (
NF-kappaB)
DNA-binding activity. We also found that knockdown of
survivin expression by
small interfering RNA transfection increased DIM-induced cell growth inhibition and apoptosis, whereas overexpression of
survivin by
cDNA transfection abrogated DIM-induced cell growth inhibition and apoptosis in both
prostate cancer cells. Importantly,
luciferase assays showed a significant reduction of
survivin-Luc and
NF-kappaB-Luc activity in
prostate cancer cells exposed to DIM and
Taxotere. Furthermore, combination treatment significantly inhibited C4-2B bone
tumor growth, and the results were correlated with the down-regulation of
survivin. From these results, we conclude that inactivation of
survivin by DIM enhanced the therapeutic efficacy of
Taxotere in
prostate cancer in general, which could be useful for the treatment of HRPC and metastatic
prostate cancer.