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Allosteric Antagonist Modulation of TRPV2 by Piperlongumine Impairs Glioblastoma Progression

ABSTRACT: Allosteric Antagonist Modulation of TRPV2 by Piperlongumine Impairs Glioblastoma Progression

PROVIDER: PRJNA544318 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR9110260_1.fastq.gz	Fastqsanger.gz
	SRR9110260_2.fastq.gz	Fastqsanger.gz
	SRR9110270_1.fastq.gz	Fastqsanger.gz
	SRR9110270_2.fastq.gz	Fastqsanger.gz
	SRR9110261_1.fastq.gz	Fastqsanger.gz

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Allosteric Antagonist Modulation of TRPV2 by Piperlongumine Impairs Glioblastoma Progression

Project description:Using machine learning to identify biological targets for natural products with anticancer properties and unknown modes of action is gaining momentum. Herein, we employ machine intelligence to deconvolute the phenotypic effects of the natural product Piperlongumine (PL) and establish an unprecedented link to allosteric modulation of the human transient receptor potential vanilloid 2 (hTRPV2) channel. Using cryo-electron microscopy (cryo-EM), we determined the structure of the PL-bound full-length rat TRPV2 channel at an overall resolution of 3.4 Å. We disclose binding of PL to a novel allosteric pocket which is responsible for a new mode of anticancer activity by PL, in particular against the aggressive glioblastoma (GBM), where TRPV2 is overexpressed. By creating CRISPRi TRPV2 knockdown GBM cells we found that the down-regulation of TRPV2 reduces sensitivity to PL and decreases ROS production. By analyzing GBM patients’ samples, we associated TRPV2 overexpression with tumor grade, disease progression and poor prognosis. Finally, formulating PL for sustained local therapy, we obtained tumor remission in a murine model of orthotopic GBM. Altogether, our strategy for target identification counter cycles established methods is broadly applicable and leverages data-motivated research hypotheses for the swift discovery of new biology and therapeutics.

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Allosteric Antagonist Modulation of TRPV2 by Piperlongumine Impairs Glioblastoma Progression.

Project description:The use of computational tools to identify biological targets of natural products with anticancer properties and unknown modes of action is gaining momentum. We employed self-organizing maps to deconvolute the phenotypic effects of piperlongumine (PL) and establish a link to modulation of the human transient receptor potential vanilloid 2 (hTRPV2) channel. The structure of the PL-bound full-length rat TRPV2 channel was determined by cryo-EM. PL binds to a transient allosteric pocket responsible for a new mode of anticancer activity against glioblastoma (GBM) in which hTRPV2 is overexpressed. Calcium imaging experiments revealed the importance of Arg539 and Thr522 residues on the antagonistic effect of PL and calcium influx modulation of the TRPV2 channel. Downregulation of hTRPV2 reduces sensitivity to PL and decreases ROS production. Analysis of GBM patient samples associates hTRPV2 overexpression with tumor grade, disease progression, and poor prognosis. Extensive tumor abrogation and long term survival was achieved in two murine models of orthotopic GBM by formulating PL in an implantable scaffold/hydrogel for sustained local therapy. Furthermore, in primary tumor samples derived from GBM patients, we observed a selective reduction of malignant cells in response to PL ex vivo. Our results establish a broadly applicable strategy, leveraging data-motivated research hypotheses for the discovery of novel means tackling cancer.

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