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Article

Harmine and Piperlongumine Revert TRIB2-Mediated Drug Resistance

1
Centre for Biomedical Research (CBMR), Universidade do Algarve, Campus of Gambelas, Building 8, Room 1.12, 8005-139 Faro, Portugal
2
Algarve Biomedical Center (ABC), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
3
Regenerative Medicine Program, Department of Biomedical Sciences and Medicine, Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
4
Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain
5
Confocal Microscopy Unit, Biotechnology Program, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain
6
Vascular Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2020, 12(12), 3689; https://doi.org/10.3390/cancers12123689
Received: 15 November 2020 / Accepted: 2 December 2020 / Published: 9 December 2020
(This article belongs to the Special Issue Pseudokinases, Tribbles Proteins and Cancer)
Poor survival and treatment failure of patients with cancer are mainly due to resistance to therapy. Tribbles homologue 2 (TRIB2) has recently been identified as a protein that promotes resistance to several anti-cancer drugs. In this study, RNA sequencing and bioinformatics analysis were used with the aim of characterizing the impact of TRIB2 on the expression of genes and developing pharmacological strategies to revert these TRIB2-mediated changes, thereby overcoming therapy resistance. We show that two naturally occurring alkaloids, harmine and piperlongumine, inverse the gene expression profile produced by TRIB2 and sensitize cancer cells to anti-cancer drugs. Our data suggest that harmine and piperlongumine or similar compounds might have the potential to overcome TRIB2-mediated therapy resistance in cancer patients.
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. View Full-Text
Keywords: TRIB2; cancer; drug resistance; FOXO; BEZ235; harmine; piperlongumine TRIB2; cancer; drug resistance; FOXO; BEZ235; harmine; piperlongumine
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MDPI and ACS Style

Machado, S.; Silva, A.; De Sousa-Coelho, A.L.; Duarte, I.; Grenho, I.; Santos, B.; Mayoral-Varo, V.; Megias, D.; Sánchez-Cabo, F.; Dopazo, A.; Ferreira, B.I.; Link, W. Harmine and Piperlongumine Revert TRIB2-Mediated Drug Resistance. Cancers 2020, 12, 3689. https://doi.org/10.3390/cancers12123689

AMA Style

Machado S, Silva A, De Sousa-Coelho AL, Duarte I, Grenho I, Santos B, Mayoral-Varo V, Megias D, Sánchez-Cabo F, Dopazo A, Ferreira BI, Link W. Harmine and Piperlongumine Revert TRIB2-Mediated Drug Resistance. Cancers. 2020; 12(12):3689. https://doi.org/10.3390/cancers12123689

Chicago/Turabian Style

Machado, Susana, Andreia Silva, Ana L. De Sousa-Coelho, Isabel Duarte, Inês Grenho, Bruno Santos, Victor Mayoral-Varo, Diego Megias, Fátima Sánchez-Cabo, Ana Dopazo, Bibiana I. Ferreira, and Wolfgang Link. 2020. "Harmine and Piperlongumine Revert TRIB2-Mediated Drug Resistance" Cancers 12, no. 12: 3689. https://doi.org/10.3390/cancers12123689

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