Gene editing and synthetically accessible inhibitors reveal role for TPC2 in HCC cell proliferation and tumor growth
Journal
Cell chemical biology
Date Issued
2021-02-11
Author(s)
Müller, Martin
Gerndt, Susanne
Chao, Yu-Kai
Zisis, Themistoklis
Nguyen, Ong Nam Phuong
Gerwien, Aaron
Urban, Nicole
Müller, Christoph
Gegenfurtner, Florian A
Geisslinger, Franz
Ortler, Carina
Zahler, Stefan
Biel, Martin
Schaefer, Michael
Grimm, Christian
Bracher, Franz
Vollmar, Angelika M
Bartel, Karin
Abstract
The role of two-pore channel 2 (TPC2), one of the few cation channels localized on endolysosomal membranes, in cancer remains poorly understood. Here, we report that TPC2 knockout reduces proliferation of cancer cells in vitro, affects their energy metabolism, and successfully abrogates tumor growth in vivo. Concurrently, we have developed simplified analogs of the alkaloid tetrandrine as potent TPC2 inhibitors by screening a library of synthesized benzyltetrahydroisoquinoline derivatives. Removal of dispensable substructures of the lead molecule tetrandrine increases antiproliferative properties against cancer cells and impairs proangiogenic signaling of endothelial cells to a greater extent than tetrandrine. Simultaneously, toxic effects on non-cancerous cells are reduced, allowing in vivo administration and revealing a TPC2 inhibitor with antitumor efficacy in mice. Hence, our study unveils TPC2 as valid target for cancer therapy and provides easily accessible tetrandrine analogs as a promising option for effective pharmacological interference.
Subjects
bisbenzyltetrahydroisoquinoline; cancer; chemical synthesis; endolysosomal cation channel; ion channel blocker; patch clamp; structural simplification; tetrandrine; tumor growth; two-pore channel 2
SDGs
Other Subjects
antineoplastic agent; calcium channel; isoquinoline derivative; TPCN2 protein, human; animal; apoptosis; C57BL mouse; cell culture; cell proliferation; chemistry; drug effect; drug screening; female; gene editing; genetics; human; liver cell carcinoma; li
Type
journal article