Details

Autor(en) / Beteiligte

• Miller, Dannah R.
• Ingersoll, Matthew A.
• Chou, Yu-Wei
• Kosmacek, Elizabeth A.
• Oberley-Deegan, Rebecca E.
• Lin, Ming-Fong

Titel

Dynamics of antioxidant heme oxygenase-1 and pro-oxidant p66Shc in promoting advanced prostate cancer progression

Ist Teil von

• Free radical biology & medicine, 2022-11, Vol.193 (Pt 1), p.274-291

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• The castration-resistant (CR) prostate cancer (PCa) is lethal and is the second leading cause of cancer-related deaths in U.S. males. To develop effective treatments toward CR PCa, we investigated reactive oxygen species (ROS) signaling pathway for its role involving in CR PCa progression. ROS can regulate both cell growth and apoptosis: a moderate increase of ROS promotes proliferation; its substantial rise results in cell death. p66Shc protein can increase oxidant species production and its elevated level is associated with the androgen-independent (AI) phenotype of CR PCa cells; while heme oxygenase-1 (HO-1) is an antioxidant enzyme and elevated in a sub-group of metastatic PCa cells. In this study, our data revealed that HO-1 and p66Shc protein levels are co-elevated in various AI PCa cell lines as well as p66Shc cDNA-transfected cells. Knockdown and/or inhibition of either p66Shc or HO-1 protein leads to reduced tumorigenicity as well as a reduction of counterpart protein. Knockdown of HO-1 alone results in increased ROS levels, nucleotide and protein oxidation and induction of cell death. Together, our data indicate that elevated HO-1 protein levels protect PCa cells from otherwise apoptotic conditions induced by aberrant p66Shc/ROS production, which thereby promotes PCa progression to the CR phenotype. p66Shc and HO-1 can serve as functional targets for treating CR PCa. [Display omitted] •HO-1 and p66Shc are co-elevated in AI PCa cells compared to corresponding AS PCa cells.•Knockdown of either protein results in a reduction of tumorigenicity of AI cells.•Knockdown or inhibition of HO-1 in AI cells results in increased ROS production and cell death.•HO-1 protects AI PCa cells from excessive ROS levels and ultimately cell death caused by aberrant p66Shc elevation.