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Article Publish Status: FREE
Abstract Title:

Harmine and Piperlongumine Revert TRIB2-Mediated Drug Resistance.

Abstract Source:

Cancers (Basel). 2020 Dec 9 ;12(12). Epub 2020 Dec 9. PMID: 33316942

Abstract Author(s):

Susana Machado, Andreia Silva, Ana Luísa De Sousa-Coelho, Isabel Duarte, Inês Grenho, Bruno Santos, Victor Mayoral-Varo, Diego Megias, Fátima Sánchez-Cabo, Ana Dopazo, Bibiana I Ferreira, Wolfgang Link

Article Affiliation:

Susana Machado

Abstract:

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.

Study Type : In Vitro Study

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