Increased manganese superoxide dismutase (SOD-2) is part of the mechanism for prostate tumor suppression by Mac25/insulin-like growth factor binding-protein-related protein-1

Abstract

Increased expression of mac25/insulin-like growth factor binding-protein related protein-1 (IGFBP-rP1) in human breast and prostate epithelial cell lines results in the suppression of tumor growth. CDNA expression array analysis revealed increased manganese superoxide dismutase (SOD-2) expression in the mac25/IGFBP-rP1-transfected M12 human prostate cancer cell line compared to M12 control cells. SOD-2 has been postulated to be a tumor suppressor. SOD-2 was also increased in LNCaP cells stably transfected with mac25/IGFBP-rP1, but not in mac25/IGFBP-rP1-transfected PC-3 cells. Mac25 LNCaP cells had a marked decrease in tumor growth in nude mice compared to controls, but there was no difference in tumor growth in mac25 PC-3 cells compared to control. Phosphorylated Erk and Akt were increased in the M12 and LNCaP transfected mac25/ IGFBP-rP1 cells but not PC-3 mac25. Inhibition of PI-3 kinase results in a marked decrease in viability of the M12-mac25 cells compared to M12 controls. Cells treated with H 2 O 2 result in an increase in phospho-ERK. Transfection of SOD-2 in M12 cells markedly decreased tumor growth, apoptosis, G1 delay in the cell cycle, and expression of senescence associated b-galactosidase. These results suggest that one of the downstream mediators of the senescence-associated tumor suppression effect of mac25/IGFBP-rP1 is SOD-2.

Suppression of growth and tumorigenicity in the prostate tumor cell line M12 by overexpression of the transcription factor SOX9

“…cDNA array analysis performed in our laboratory had indicated potential regulation of SOX9 in M12 cells which overproduce mac25 following transfection with mac25 cDNA (Plymate et al, 2003). These results were confirmed by Northern blot analysis, as shown in Figure 1a.…”

“…MnSOD2 acts as a tumor suppressor in M12 cells (Plymate et al, 2003). The mechanism of action for mac25 is unknown, but it has been shown to translocate to the nucleus and may act as a transcription factor (Wilson et al, 2001).…”

“…As a first step in the identification of genes induced by mac25 expression in prostate epithelial cells, we have performed cDNA array analysis of M12 cells overexpressing IGFBP-rP1/mac25, and on M12 cells transfected with empty vector (Plymate et al, 2003). Among several gene products determined to be upregulated in M12/mac25 cells was the transcription factor SOX9, a critical protein in male gonadal development and in chondrogenesis.…”

Functional Variant of Manganese Superoxide Dismutase (SOD2 V16A) Polymorphism Is Associated with Prostate Cancer Risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Study

“…SOD2 plays a pivotal role in protecting cells from reactive oxygen species -induced oxidative damage and is a known tumor suppressor in prostate cancer cells (1,(3)(4)(5). The Ala variant of SOD2 allows more efficient SOD2 import into the mitochondrial matrix and generates more active SOD2 compared with the Val variant (14)(15)(16).…”

“…Among the three isoforms of SOD (SOD1, CuZn-SOD; SOD2, MnSOD; and SOD3, EC-SOD), SOD2 plays an important role as a primary mitochondria antioxidant enzyme and suppresses the growth of prostate cancer cells (1,(3)(4)(5). In this gene, several polymorphisms have been found, including Ex2+24T>C (V16A), which has been widely evaluated for association with various cancers, including prostate cancer (6)(7)(8)(9)(10)(11)(12)(13).…”