Tumor suppressor activity of ODC antizyme in MEK-driven skin tumorigenesis

Abstract

To test the hypothesis that suppression of ornithine decarboxylase (ODC) activity blocks the promotion of target cells in the outer root sheath of the hair follicle initiated by Raf/MEK/ERK activation, we crossed mice overexpressing an activated MEK mutant in the skin (K14-MEK mice) with two transgenic lines overexpressing antizyme (AZ), which binds to ODC and targets it for degradation. K14-MEK mice develop spontaneous skin tumors without initiation or promotion. These mice on the ICR background were crossed with K5-AZ and K6-AZ mice on both the carcinogenesis-resistant C57BL/6 background and the sensitive DBA/2 background. Expression of AZ driven by either the K5 or K6 promoter along with K14-MEK dramatically delayed tumor incidence and reduced tumor multiplicity on both backgrounds compared with littermates expressing the MEK transgene alone. The effect was most remarkable in the MEK/K6-AZ mice from the ICR/D2 F1 cross, where double transgenic mice averaged less than one tumor per mouse for more than 8 weeks, while K14-MEK mice averaged over 13 tumors per mouse at this age. Putrescine was decreased in MEK/AZ tumors, while spermidine and spermine levels were unaffected, suggesting that the primary role played by AZ in this system is to inhibit putrescine accumulation. MEK/AZ tumors did not show evidence of apoptosis, but there was a 15-20% decrease in S-phase cells and a 40-60% decrease in mitotic cells in MEK/AZ tumors. These results indicate that the principal effect of AZ may be to slow cell growth primarily by increasing G2/M transit time.

Ras Transformation of RIE-1 Cells Activates Cap-Independent Translation of Ornithine Decarboxylase: Regulation by the Raf/MEK/ERK and Phosphatidylinositol 3-Kinase Pathways

“…Increased ODC activity is necessary for transformation induced either by the direct activation of the Ras oncogene or by activation of downstream targets such as MEK (6,14,33,34). Although studies Twenty-four hours after transfection, luciferase activities were measured (A) and cell cycle progression was analyzed (B and C ) as described in Fig.…”

Antizyme and antizyme inhibitor, a regulatory tango

“…As antizyme is capable of inhibiting ODC and polyamine uptake, it is not surprising that antizyme acts as a negative regulator of cellular proliferation and of tumor development both when overexpressed in cultured cells and in transgenic mice [69][70][71][72][73][74]. In some systems, forced antizyme expression provokes apoptotic cell death [70,71,75,76].…”

Antizyme, a natural ornithine decarboxylase inhibitor, induces apoptosis of haematopoietic cells through mitochondrial membrane depolarization and caspases’ cascade

“…They participate in the crucial roles in molecular and cellular functions, including developmental regulation, cell cycle, proliferation, cell death, differentiation and tumorigenesis [16][17][18][19][20]. Antizyme-mediated degradation of ODC is conserved from yeast to humans [21], however an unique feature such as the +1 frameshifting is required for functional antizyme production in mammalian [22].…”