Browsing by Author "Restovic, Franko"

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    Targeting antisense mitochondrial ncRNAs inhibits murine melanoma tumor growth and metastasis through reduction in survival and invasion factors
    (IMPACT JOURNALS LLC, 2016) Lobos Gonzalez, Lorena; Silva, Veronica; Araya, Mariela; Restovic, Franko; Echenique, Javiera; Oliveira Cruz, Luciana; Fitzpatrick, Christopher; Briones, Macarena; Villegas, Jaime; Villota, Claudio; Vidaurre, Soledad; Borgna, Vincenzo; Socias, Miguel; Valenzuela, Sebastian; Lopez, Constanza; Socias, Teresa; Varas, Manuel; Diaz, Jorge; Burzio, Luis O.; Burzio, Veronica A.
    We reported that knockdown of the antisense noncoding mitochondrial RNAs (ASncmtRNAs) induces apoptotic death of several human tumor cell lines, but not normal cells, suggesting this approach for selective therapy against different types of cancer. In order to translate these results to a preclinical scenario, we characterized the murine noncoding mitochondrial RNAs (ncmtRNAs) and performed in vivo knockdown in syngeneic murine melanoma models. Mouse ncmtRNAs display structures similar to the human counterparts, including long double-stranded regions arising from the presence of inverted repeats. Knockdown of ASncmtRNAs with specific antisense oligonucleotides (ASO) reduces murine melanoma B16F10 cell proliferation and induces apoptosis in vitro through downregulation of pro-survival and metastasis markers, particularly survivin. For in vivo studies, subcutaneous B16F10 melanoma tumors in C57BL/6 mice were treated systemically with specific and control antisense oligonucleotides (ASO). For metastasis studies, tumors were resected, followed by systemic administration of ASOs and the presence of metastatic nodules in lungs and liver was assessed. Treatment with specific ASO inhibited tumor growth and metastasis after primary tumor resection. In a metastasis-only assay, mice inoculated intravenously with cells and treated with the same ASO displayed reduced number and size of melanoma nodules in the lungs, compared to controls. Our results suggest that ASncmtRNAs could be potent targets for melanoma therapy. To our knowledge, the ASncmtRNAs are the first potential non-nuclear targets for melanoma therapy.
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    The Glucose-Related Decrease in Polar Auxin Transport During Ripening and its Possible Role in Grapevine Berry Coloring
    (2023) Serrano, Alejandra; Kuhn, Nathalie; Restovic, Franko; Meyer-Regueiro, Carlos; Madariaga, Mónica; Arce Johnson, Jorge Patricio
    Auxin is a hormone that delays ripening in part by reducing anthocyanin content and impairing color development. Auxin content declines during the ripening process, whereas sugars accumulate from pre-veraison onwards. The spatio-temporal distribution of this hormone depends in part on polar auxin transport. On the other hand, sugar, acting as a signal molecule, modulates auxin distribution in model organisms; however, its efect on polar auxin transport during the coloring process in grapevine berries has not been investigated. To address this issue, we characterized auxin transport and sugar variations during the ripening process and performed treatments intended to alter auxin homeostasis in grape fruits. We found that polar auxin transport declines in concert with increasing sugar content prior to and at veraison. Moreover, N-1-napthylphthalamic acid (NPA; a polar auxin transport inhibitor) and glucose treatment increased berry coloration, reduced polar auxin transport and VvPIN1 transcript abundance at pre-veraison, and combined NPA and glucose treatment further increased berry color compared to glucose and NPA alone. Indole-3-acetic acid (IAA) treatment prevented the negative efect of glucose on auxin transport, suggesting that auxin homeostasis might be relevant for glucose modulation of berry ripening in grapevine. Impaired auxin transport is associated with increased ethylene sensitivity in several plant processes, including fruit abscission. For exploring a potential involvement of the ethylene pathway during the coloring process, we analyzed the transcript abundance of the putative ethylene receptor, VvETR2, a possible negative regulator of the ethylene pathway. We found that glucose plus NPA treatment reduced VvETR2 transcript abundance, whose expression is reported to decline from veraison onwards. Our results suggest a possible mechanism in which a rise in glucose contributes to auxin transport inhibition in coloring berries. As glucose has been reported to promote ripening and IAA inhibits berry coloring, our results further support an antagonistic switch between IAA and glucose, that could also involve changes in the expression of the VvETR2 gene