MnSOD drives neuroendocrine differentiation, androgen independence, and cell survival in prostate cancer cells

An increase in neuroendocrine (NE) cell number has been associated with progression of prostate tumor, one of the most frequent cancers among Western males. We previously reported that mitochondrial manganese superoxide dismutase (MnSOD) increases during the NE differentiation process. The goal of this study was to find whether MnSOD up-regulation is enough to induce NE differentiation. Several human prostate cancer LNCaP cell clones stably overexpressing MnSOD were characterized and two were selected (MnSOD-S4 and MnSOD-S12). MnSOD overexpression induces NE morphological features as well as coexpression of the NE marker synaptophysin. Both MnSOD clones exhibit lower superoxide levels and higher H2O2 levels. MnSOD-overexpressing cells show higher proliferation rates in complete medium, but in steroid-free medium MnSOD-S12 cells are still capable of proliferation. MnSOD up-regulation decreases androgen receptor and prevents its nuclear translocation. MnSOD also induces up-regulation of Bcl-2 and prevents docetaxel-, etoposide-, or TNF-induced cell death. Finally, MnSOD-overexpressing cells enhance growth of androgen-independent PC-3 cells but reduce growth of androgen-dependent cells. These results indicate that redox modulation caused by MnSOD overexpression explains most NE-like features, including morphological changes, NE marker expression, androgen independence, inhibition of apoptosis, and enhancement of cell growth. Many of these events can be associated with the androgen dependent-independent transition during prostate cancer progression.