2. Academic Validation
  3. PPT1 Promotes Tumor Growth and Is the Molecular Target of Chloroquine Derivatives in Cancer

PPT1 Promotes Tumor Growth and Is the Molecular Target of Chloroquine Derivatives in Cancer

  • Cancer Discov. 2019 Feb;9(2):220-229. doi: 10.1158/2159-8290.CD-18-0706.
Vito W Rebecca  # 1,  Michael C Nicastri  # 2,  Colin Fennelly 1,  Cynthia I Chude 1,  Julie S Barber-Rotenberg 3,  Amruta Ronghe 4,  Quentin McAfee 1,  Noel P McLaughlin 2,  Gao Zhang 4,  Aaron R Goldman 4,  Rani Ojha 1,  Shengfu Piao 1,  Estela Noguera-Ortega 1,  Alessandra Martorella 4,  Gretchen M Alicea 4,  Jennifer J Lee 1,  Lynn M Schuchter 1,  Xiaowei Xu 5,  Meenhard Herlyn 4,  Ronen Marmorstein 3,  Phyllis A Gimotty 6,  David W Speicher 4,  Jeffrey D Winkler 7,  Ravi K Amaravadi 8
Affiliations

Affiliations

  • 1 Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 2 Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 3 Department of Biochemistry and Biophysics, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 4 Molecular and Cellular Oncogenesis Program and Melanoma Research Center, Wistar Institute, Philadelphia, Pennsylvania.
  • 5 Department of Pathology, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 6 Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 7 Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania. Winkler@sas.upenn.edu Ravi.amaravadi@uphs.upenn.edu.
  • 8 Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Winkler@sas.upenn.edu Ravi.amaravadi@uphs.upenn.edu.
  • # Contributed equally.
PMID: 30442709 DOI: 10.1158/2159-8290.CD-18-0706
Abstract

Clinical trials repurposing lysosomotropic chloroquine (CQ) derivatives as Autophagy inhibitors in Cancer demonstrate encouraging results, but the underlying mechanism of action remains unknown. Here, we report a novel dimeric CQ (DC661) capable of deacidifying the lysosome and inhibiting Autophagy significantly better than hydroxychloroquine (HCQ). Using an in situ photoaffinity pulldown strategy, we identified palmitoyl-protein thioesterase 1 (PPT1) as a molecular target shared across monomeric and dimeric CQ derivatives. HCQ and Lys05 also bound to and inhibited PPT1 activity, but only DC661 maintained activity in acidic media. Knockout of PPT1 in Cancer cells using CRISPR/Cas9 editing abrogates Autophagy modulation and cytotoxicity of CQ derivatives, and results in significant impairment of tumor growth similar to that observed with DC661. Elevated expression of PPT1 in tumors correlates with poor survival in patients in a variety of cancers. Thus, PPT1 represents a new target in Cancer that can be inhibited with CQ derivatives. SIGNIFICANCE: This study identifies PPT1 as the previously unknown lysosomal molecular target of monomeric and dimeric CQ derivatives. Genetic suppression of PPT1 impairs tumor growth, and PPT1 levels are elevated in Cancer and associated with poor survival. These findings provide a strong rationale for targeting PPT1 in Cancer. This article is highlighted in the In This Issue feature, p. 151.

Figures
Products