2026-05-20T03:47:31Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/132432024-09-27T10:12:47Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19607
Repisalud
author
Machado, Susana
author
Silva, Andreia
author
De Sousa-Coelho, Ana Luísa
author
Duarte, Isabel
author
Grenho, Ines
author
Santos, Bruno
author
Mayoral-Varo, Victor
author
Megias Vazquez, Diego
author
Sanchez-Cabo, Fatima
author
Dopazo, Ana
author
Ferreira, Bibiana I
author
Link, Wolfgang
funder
Fundação para a Ciência e Tecnologia (Portugal)
funder
Ministerio de Ciencia, Innovación y Universidades (España)
funder
Unión Europea. Comisión Europea. H2020
2021-07-15T11:04:08Z
2021-07-15T11:04:08Z
2020-12-09
Cancers (Basel). 2020; 12(12):3689
10.3390/cancers12123689
2072-6694
Cancers
33316942
http://hdl.handle.net/20.500.12105/13243
Therapy resistance is responsible for most relapses in patients with cancer and is the major challenge to improving the clinical outcome. The pseudokinase Tribbles homologue 2 (TRIB2) has been characterized as an important driver of resistance to several anti-cancer drugs, including the dual ATP-competitive PI3K and mTOR inhibitor dactolisib (BEZ235). TRIB2 promotes AKT activity, leading to the inactivation of FOXO transcription factors, which are known to mediate the cell response to antitumor drugs. To characterize the downstream events of TRIB2 activity, we analyzed the gene expression profiles of isogenic cell lines with different TRIB2 statuses by RNA sequencing. Using a connectivity map-based computational approach, we identified drug-induced gene-expression profiles that invert the TRIB2-associated expression profile. In particular, the natural alkaloids harmine and piperlongumine not only produced inverse gene expression profiles but also synergistically increased BEZ235-induced cell toxicity. Importantly, both agents promote FOXO nuclear translocation without interfering with the nuclear export machinery and induce the transcription of FOXO target genes. Our results highlight the great potential of this approach for drug repurposing and suggest that harmine and piperlongumine or similar compounds might be useful in the clinic to overcome TRIB2-mediated therapy resistance in cancer patients.
eng
Harmine and Piperlongumine Revert TRIB2-Mediated Drug Resistance.
journal article
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HarmineandPiperlongumineRevert_2020.pdf.txt