Abstract
BackgroundAndrogen signaling plays a critical role in the development of prostate cancer and its progression. However, androgen-independent prostate cancer cells emerge after hormone ablation therapy, resulting in significant clinical problems. We have previously demonstrated that the HOXB13 homeodomain protein functions as a prostate cancer cell growth suppressor by inhibiting androgen-mediated signals. However, the role of the HOXB13 in androgen-independent growth of prostate cancer cells remains unexplained.ResultsIn this report, we first demonstrated that HOXB13 was highly overexpressed in hormone-refractory tumors compared to tumors without prostate-specific antigen after initial treatment. Functionally, in an androgen-free environment minimal induction of HOXB13 in LNCaP prostate cancer cells, to the level of the normal prostate, markedly promoted cell proliferation while suppression inhibited cell proliferation. The HOXB13-mediated cell growth promotion in the absence of androgen, appears to be mainly accomplished through the activation of RB-E2F signaling by inhibiting the expression of the p21waf tumor suppressor. Indeed, forced expression of HOXB13 dramatically decreased expression of p21waf; this inhibition largely affected HOXB13-mediated promotion of E2F signaling.ConclusionsTaken together, the results of this study demonstrated the presence of a novel pathway that helps understand androgen-independent survival of prostate cancer cells. These findings suggest that upregulation of HOXB13 is associated with an additive growth advantage of prostate cancer cells in the absence of or low androgen concentrations, by the regulation of p21-mediated E2F signaling.
Highlights
Androgen signaling plays a critical role in the development of prostate cancer and its progression
There are no anti-HOXB13 antibodies suitable for immunohistochemistry that can be purchased in the commercial market
HOXB13 was detected in the nuclear compartment of HOXB13-positive LNCaP and MDAPCa2b cells, but not in the HOXB13-negative PC3 and DU145 cells; these findings suggested that antibodies did not react to the native form of the 50 kDa protein observed in the Western blot
Summary
Androgen signaling plays a critical role in the development of prostate cancer and its progression. Androgen-independent prostate cancer cells emerge after hormone ablation therapy, resulting in significant clinical problems. We have previously demonstrated that the HOXB13 homeodomain protein functions as a prostate cancer cell growth suppressor by inhibiting androgen-mediated signals. Androgen ablation therapy is the frontline treatment for metastatic PCa; the clinical response is transient, resulting in the recurrence of tumors. These androgen-independent (AI) tumors paradoxically depend on the AR [11,12], suggesting that AR-mediated signaling is required for the growth of cancer cells, even when absent or present only in low concentrations. There is evidence to support a link between the role of HOXB13 and the malignant progression of PCa
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