Allosteric Antagonist Modulation of TRPV2 by Piperlongumine Impairs Glioblastoma Progression

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.