Although androgen excess is considered detrimental to women's health and fertility, global and ovarian granulosa cell-specific androgen-receptor (AR) knockout mouse models have been used to show that androgen actions through ARs are actually necessary for normal ovarian function and female fertility. Here we describe two AR-mediated pathways in granulosa cells that regulate ovarian follicular development and therefore female fertility. First, we show that androgens attenuate follicular atresia through nuclear and extranuclear signaling pathways by enhancing expression of the microRNA (miR) miR-125b, which in turn suppresses proapoptotic protein expression. Second, we demonstrate that, independent of transcription, androgens enhance follicle-stimulating hormone (FSH) receptor expression, which then augments FSHmediated follicle growth and development. Interestingly, we find that the scaffold molecule paxillin regulates both processes, making it a critical regulator of AR actions in the ovary. Finally, we report that low doses of exogenous androgens enhance gonadotropin-induced ovulation in mice, further demonstrating the critical role that androgens play in follicular development and fertility. These data may explain reported positive effects of androgens on ovulation rates in women with diminished ovarian reserve. Furthermore, this study demonstrates mechanisms that might contribute to the unregulated follicle growth seen in diseases of excess androgens such as polycystic ovary syndrome. O ther than the obligatory role of androgens as estrogen precursors in steroidogenesis (1), little is known about the direct involvement of androgens in the female ovary. For many decades, excess androgens in women have been considered detrimental to women's health, as diseases such as polycystic ovary syndrome (PCOS) are associated with reduced fertility. In the past, these negative effects of androgens on female fertility were thought to occur primarily at the level of the hypothalamus and pituitary (2, 3), although important data across different species (4-7) suggested that androgens could also directly promote follicle growth (8, 9). Attitudes about androgen actions in female fertility changed with the development of global androgenreceptor knockout (ARKO) mice (10-12). The female ARKO mice had considerable reproductive defects, with decreased fertility, defective follicular development, reduced ovulation, and premature ovarian failure. In other words, the phenotype of these ARKO mice suggested that androgen signaling might actually be important for normal female reproductive health. Intriguingly, through the generation of granulosa cell (GC)-specific ARKO mice, we (13) and then others (14) demonstrated that essentially all the observed reproductive phenotypes in the complete AR-null mice are caused by androgen actions in GCs. These results highlighted that, with regard to fertility, androgen signaling in the ovary is at least as important as androgen signaling in the pituitary or hypothalamus. By using this GC-specific ARK...

Victoria Fellowship (Government of Victoria, Australia); CRB Blackburn Scholarship (Royal Australasian College of Physicans); Overseas Research Experience Scholarship, University of Melbourne.

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Chemotherapy is an adjuvant treatment for glioblastomas, however, chemotherapy remains palliative because of the development of multidrug resistance (MDR). Following prolonged chemotherapy, MDR protein 1 (MDR1) and CD133 increase in recurrent glioblastomas. CD133 positive (CD133+) glioma cancer stem-like cells (GCSCs) markedly promote drug resistance and exhibit increased DNA damage repair capability; thus they have a key role in determining tumor chemosensitivity. Although CD133, DNA-dependent protein kinase (DNA-PK), and MDR1 are elevated in CD133+ GCSCs, the relationship among these molecules has not been elucidated. In this study, MDR glioblastoma cell lines were created in response to prolonged doxorubicin chemotherapy. CD133, DNA-PK and MDR1 were markedly elevated in these cells. CD133 and DNA-PK may increase MDR1 via the phosphatidylinositol-3-kinase (PI3K)-Akt signal pathway. PI3K downstream targets Akt and nuclear factor (NF)-κB, which interacts with the MDR1 promoter, were also elevated in these cells. Downregulation of CD133 and DNA-PK by small interfering RNA, or inhibition of PI3K or Akt, decreased Akt, NF-κB and MDR1 expression. The results indicate that CD133 and DNA-PK regulate MDR1 through the PI3K- or Akt-NF-κB signal pathway. Consequently, a novel chemotherapeutic regimen targeting CD133 and DNA-PK in combination with traditional protocols may increase chemotherapeutic efficacy and improve prognosis for individuals who present with glioblastoma.