2. Academic Validation
  3. Gene editing and synthetically accessible inhibitors reveal role for TPC2 in HCC cell proliferation and tumor growth

Gene editing and synthetically accessible inhibitors reveal role for TPC2 in HCC cell proliferation and tumor growth

  • Cell Chem Biol. 2021 Aug 19;28(8):1119-1131.e27. doi: 10.1016/j.chembiol.2021.01.023.
Martin Müller 1,  Susanne Gerndt 2,  Yu-Kai Chao 3,  Themistoklis Zisis 1,  Ong Nam Phuong Nguyen 1,  Aaron Gerwien 4,  Nicole Urban 5,  Christoph Müller 2,  Florian A Gegenfurtner 1,  Franz Geisslinger 1,  Carina Ortler 1,  Cheng-Chang Chen 6,  Stefan Zahler 1,  Martin Biel 7,  Michael Schaefer 5,  Christian Grimm 8,  Franz Bracher 9,  Angelika M Vollmar 10,  Karin Bartel 11
Affiliations

Affiliations

  • 1 Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University Munich, 81377 Munich, Germany.
  • 2 Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-University Munich, 81377 Munich, Germany.
  • 3 Walther-Straub-Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University Munich, 80336 Munich, Germany.
  • 4 Department of Chemistry and Munich Center for Integrated Protein Science (CIPSM), Ludwig-Maximilians-University Munich, 81377 Munich, Germany.
  • 5 Rudolf-Boehm-Institute of Pharmacology and Toxicology, Leipzig University, 04107 Leipzig, Germany.
  • 6 Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, 100 Taipei, Taiwan.
  • 7 Department of Pharmacy, Pharmacology, Ludwig-Maximilians-University Munich, 81377 Munich, Germany.
  • 8 Walther-Straub-Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University Munich, 80336 Munich, Germany. Electronic address: [email protected].
  • 9 Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-University Munich, 81377 Munich, Germany. Electronic address: [email protected].
  • 10 Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University Munich, 81377 Munich, Germany. Electronic address: [email protected].
  • 11 Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University Munich, 81377 Munich, Germany. Electronic address: [email protected].
PMID: 33626324 DOI: 10.1016/j.chembiol.2021.01.023
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.

Keywords

bisbenzyltetrahydroisoquinoline; cancer; chemical synthesis; endolysosomal cation channel; ion channel blocker; patch clamp; structural simplification; tetrandrine; tumor growth; two-pore channel 2.

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