Reactive oxygen species (ROS) and the coupled oxidative stress have been associated with tumor formation. Several studies suggested that ROS can act as secondary messengers and control various signaling cascades. In the present studies, we characterized the oxidative stress status in three different prostate cancer cells (PC3, DU145, and LNCaP) exhibiting various degree of aggressiveness and normal prostate cells in culture (WPMY1, RWPE1, and primary cultures of normal epithelial cells). We observed increased ROS generation in cancer cells compared with normal cells, and that extramitochondrial source of ROS generator, NAD(P)H oxidase (Nox) systems, are associated with the ROS generation and are critical for the malignant phenotype of prostate cancer cells. Moreover, diphenyliodonium, a specific Nox inhibitor, blocked proliferation, modulated the activity of growth signaling cascades extracellular signal-regulated kinase (ERK)1/ERK2 and p38 mitogen-activated protein kinase as well as AKT protein kinaseB, and caused cyclin B-dependent G 2 -M cell cycle arrest. We also observed higher degrees of ROS generation in the PC3 cells than DU145 and LNCaP, and that ROS generation is critical for migratory/invasiveness phenotypes. Furthermore, blocking of the ROS production rather than ROS neutralization resulted in decreased matrix metalloproteinase 9 activity as well as loss of mitochondrial potential, plausible reasons for decreased cell invasion and increased cell death. Taken together, these studies show, for the first time, the essential role of ROS production by extramitochondrial source in prostate cancer and suggest that therapies aimed at reducing ROS production might offer effective means of combating prostate cancer in particular, and perhaps other malignancies in general.

As prostate cancer and aberrant changes in reactive oxygen species (ROS) become more common with aging, ROS signaling may play an important role in the development and progression of this malignancy. Increased ROS, otherwise known as oxidative stress, is a result of either increased ROS generation or a loss of antioxidant defense mechanisms. Oxidative stress is associated with several pathological conditions including inflammation and infection. ROS are products of normal cellular metabolism and play vital roles in stimulation of signaling pathways in response to changing intraand extracellular environmental conditions. Chronic increases in ROS over time are known to induce somatic mutations and neoplastic transformation. In this review we summarize the causes for increased ROS generation and its potential role in etiology and progression of prostate cancer.

In transitional cell carcinoma, the most common form of bladder cancer, overexpression of the matrix metalloproteinases MMP-2 and MMP-9 offers prognostic value as markers of disease-specific survival. These molecules have been implicated in metastasis of bladder cancer, but the underlying mechanisms through which they are controlled are poorly defined. In this study, we investigated a role of p38 mitogen-activated protein kinase (MAPK) in this process, using bladder cancer cell lines HTB9 and HTB5 that were derived from different tumor stages. p38 MAPK modulated MMP-2/9 mRNA levels at the levels of transcript stability and MMP-2/9 activity along with invasive capacity. We defined a downstream effector of p38 MAPK, MAPKactivated protein kinase 2 (MAPKAPK2), that was associated with MMP-2/9 activation. Ectopic expression of wild-type or constitutively active forms of MAPKAPK2 increased MMP-2/9 activities and invasive capacity. Conversely, p38 MAPK inhibition blocked the MAPKAPK2-mediated increase in MMP-2/9 activities and the invasive capacity of the cancer cells. Our findings implicate p38 MAPK and MAPKAPK2 in mediating bladder cancer invasion via regulation of MMP-2 and MMP-9 at the level of mRNA stability. Cancer Res; 70(2); 832-41.

No abstract