Journal article
A Novel Inhibitor of HSP70 Induces Mitochondrial Toxicity and Immune Cell Recruitment in Tumors
Cancer research (Chicago, Ill.), v 80(23), pp 5270-5281
01 Dec 2020
PMID: 33023943
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The protein chaperone HSP70 is overexpressed in many cancers including colorectal cancer, where overexpression is associated with poor survival. We report here the creation of a uniquely acting HSP70 inhibitor (HSP70i) that targets multiple compartments in the cancer cell, including mitochondria. This inhibitor was mitochondria toxic and cytotoxic to colorectal cancer cells, but not to normal colon epithelial cells. Inhibition of HSP70 was efficacious as a single agent in primary and metastatic models of colorectal cancer and enabled identification of novel mitochondrial client proteins for HSP70. In a syngeneic colorectal cancer model, the inhibitor increased immune cell recruitment into tumors. Cells treated with the inhibitor secreted danger-associated molecular patterns (DAMP), including ATP and HMGB1, and functioned effectively as a tumor vaccine. Interestingly, the unique properties of this HSP70i in the disruption of mitochondrial function and the inhibition of proteostasis both contributed to DAMP release. This HSP70i constitutes a promising therapeutic opportunity in colorectal cancer and may exhibit antitumor activity against other tumor types. SIGNIFICANCE: These findings describe a novel HSP70i that disrupts mitochondrial proteostasis, demonstrating single-agent efficacy that induces immunogenic cell death in treated tumors.
Metrics
Details
- Title
- A Novel Inhibitor of HSP70 Induces Mitochondrial Toxicity and Immune Cell Recruitment in Tumors
- Creators
- Thibaut Barnoud - The Wistar InstituteJessica C Leung - The Wistar InstituteJulia I-Ju Leu - Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PennsylvaniaSubhasree Basu - The Wistar InstituteAdi Narayana Reddy Poli - The Wistar InstituteJoshua L D Parris - Department of Graduate Group in Cell and Molecular Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PennsylvaniaAlexandra Indeglia - University of PennsylvaniaTetyana Martynyuk - Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, PennsylvaniaMadeline Good - The Wistar InstituteKeerthana Gnanapradeepan - University of PennsylvaniaEmilio Sanseviero - The Wistar InstituteRebecca Moeller - Drexel University, Hematology and OncologyHsin-Yao Tang - The Wistar InstituteJoel Cassel - Protein Express (United States)Andrew V Kossenkov - The Wistar InstituteQin Liu - The Wistar InstituteDavid W Speicher - The Wistar InstituteDmitry I Gabrilovich - Department of Graduate Group in Cell and Molecular Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PennsylvaniaJoseph M Salvino - Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania. mmurphy@wistar.org jsalvino@wistar.orgDonna L George - Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PennsylvaniaMaureen E Murphy - The Wistar Institute
- Publication Details
- Cancer research (Chicago, Ill.), v 80(23), pp 5270-5281
- Grant note
- F32 CA220972 / NCI NIH HHS T32 CA009171 / NCI NIH HHS S10 OD023658 / NIH HHS P01 CA114046 / NCI NIH HHS P30 CA010815 / NCI NIH HHS K99 CA241367 / NCI NIH HHS R01 CA139319 / NCI NIH HHS S10 OD021669 / NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- College of Medicine; Hematology and Oncology
- Web of Science ID
- WOS:000596730000012
- Scopus ID
- 2-s2.0-85100333608
- Other Identifier
- 991021860783304721
UN Sustainable Development Goals (SDGs)
This publication has contributed to the advancement of the following goals:
InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Oncology