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

Rebecca, Vito W.; Nicastri, Michael C.; Fennelly, Colin; Chude, Cynthia I.; Barber‐Rotenberg, Julie S.; Ronghe, Amruta; McAfee, Quentin; McLaughlin, Noel P.; Zhang, Gao; Goldman, Aaron R.; Ojha, Rani; Piao, Shengfu; Noguera-Ortega, Estela; Martorella, Alessandra; Alicea, Gretchen M.; Lee, Jennifer J.; Schuchter, Lynn M.; Xu, Xiaowei; Herlyn, Meenhard; Marmorstein, Ronen; Gimotty, Phyllis A.; Speicher, David W.; Winkler, Jeffrey D.; Amaravadi, Ravi K.

doi:10.1158/2159-8290.cd-18-0706

Cited by 170 publications

(188 citation statements)

References 26 publications

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“…Efforts to improve drug delivery of HCQ using liposomal or nanoparticle encapsulation technology to address this issue as well as stromal interference are under way (139). Meanwhile, dimeric chloroquines and dimeric quinacrines (see below) may address this issue because they have superior cell penetration and lysosomal localization compared with HCQ in the acidic tumor microenvironment (140).…”

Section: Repurposing Hcq In Clinical Oncology Trialsmentioning

confidence: 99%

“…CQ derivatives such as HCQ for cancer has been limited by a missing molecular target. A series of more potent dimeric compounds based on chloroquines and quinacrines have been generated including Lys05 (151), DQ661 (152), and DC661 (140). The dimeric chloroquine Lys05 has been shown to have significant antitumor activity in vivo in multiple tumor models.…”

Section: Atg4b Inhibitorsmentioning

confidence: 99%

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Targeting Autophagy in Cancer: Recent Advances and Future Directions

2019

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Autophagy, a multistep lysosomal degradation pathway that supports nutrient recycling and metabolic adaptation, has been implicated as a process that regulates cancer. Although autophagy induction may limit the development of tumors, evidence in mouse models demonstrates that autophagy inhibition can limit the growth of established tumors and improve response to cancer therapeutics. Certain cancer genotypes may be especially prone to autophagy inhibition. Different strategies for autophagy modulation may be needed depending on the cancer context. Here, we review new advances in the molecular control of autophagy, the role of selective autophagy in cancer, and the role of autophagy within the tumor microenvironment and tumor immunity. We also highlight clinical efforts to repurpose lysosomal inhibitors, such as hydroxychloroquine, as anticancer agents that block autophagy, as well as the development of more potent and specifi c autophagy inhibitors for cancer treatment, and review future directions for autophagy research. Signifi cance: Autophagy plays a complex role in cancer, but autophagy inhibition may be an effective therapeutic strategy in advanced cancer. A deeper understanding of autophagy within the tumor microenvironment has enabled the development of novel inhibitors and clinical trial strategies. Challenges and opportunities remain to identify patients most likely to benefi t from this approach.

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Section: Repurposing Hcq In Clinical Oncology Trialsmentioning

confidence: 99%

Section: Atg4b Inhibitorsmentioning

confidence: 99%

Targeting Autophagy in Cancer: Recent Advances and Future Directions

2019

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“…However, there are limitations in the use of hydroxychloroquine, since it inhibits lysosome function, in addition to its effects on autophagy. Until recently, the mechanism of action of hydroxychloroquine and derivatives has been unclear, but it is now thought to inhibit the lysosomal enzyme palmitoyl-protein thioesterase 1, which may account for the observed effects on autophagy in cancer [28]. However, the potency and pharmacology of hydroxychloroquine, as well as its inherent basicity, are a concern for drug development [4,29,30].…”

Section: Introductionmentioning

confidence: 99%

On ATG4B as Drug Target for Treatment of Solid Tumours—The Knowns and the Unknowns

Agrotis

Ketteler

2019

Cells

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Autophagy is an evolutionary conserved stress survival pathway that has been shown to play an important role in the initiation, progression, and metastasis of multiple cancers; however, little progress has been made to date in translation of basic research to clinical application. This is partially due to an incomplete understanding of the role of autophagy in the different stages of cancer, and also to an incomplete assessment of potential drug targets in the autophagy pathway. While drug discovery efforts are on-going to target enzymes involved in the initiation phase of the autophagosome, e.g., unc51-like autophagy activating kinase (ULK)1/2, vacuolar protein sorting 34 (Vps34), and autophagy-related (ATG)7, we propose that the cysteine protease ATG4B is a bona fide drug target for the development of anti-cancer treatments. In this review, we highlight some of the recent advances in our understanding of the role of ATG4B in autophagy and its relevance to cancer, and perform a critical evaluation of ATG4B as a druggable cancer target.

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“…At present, some researchers explored the possibility of regulating Ras tumorigenesis by targeting palmitoylation to disrupt the membrane interaction of specific Ras isoform [18]. Studies have shown that, PPT1 promotes tumor progression and serves as the molecular target of drugs in cancer, targeting PPT1 blocks mTOR signaling and concurrently inhibits autophagy in a different way from catalytic inhibitors, thus provides a new strategy for cancer treatment [19,20]. However, the study of PPT2 in cancer has rarely been reported.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of PPT2 Represses the Clear Cell Renal Cell Carcinoma Progression by Reducing Epithelial-to-mesenchymal Transition

et al. 2020

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Clear cell renal cell carcinoma (ccRCC) is one of the most common malignant tumors of the urinary system and has a poor response to radiotherapy and chemotherapy. To date, it is urgent to find effective biomarkers for the prevention and treatment of ccRCC. The occurrence and development of ccRCC is closely related to metabolic disturbances. Palmitoyl protein thioesterase 2 (PPT2) is a lysosomal thioesterase which is highly associated with metabolism, and it has never been studied in ccRCC. In this study, we first revealed PPT2 is significantly downregulated in ccRCC, and its expression level is highly correlated with clinicopathological parameters of ccRCC patients. Our ROC curve analyses evaluated the potential of PPT2 as a novel diagnostic marker and prognostic factor. Functional experiment results showed overexpression of PPT2 represses the proliferation, migration and invasion of ccRCC cells in vitro. Mechanistic investigations demonstrated that overexpression of PPT2 represses the ccRCC progression by reducing epithelial-to-mesenchymal transition (EMT). In conclusion, PPT2 is downregulated in ccRCC. Decreased PPT2 expression may be considered as a novel diagnostic marker and prognostic factor and serve as a therapeutic target for ccRCC.

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

Cited by 170 publications

References 26 publications

Targeting Autophagy in Cancer: Recent Advances and Future Directions

Targeting Autophagy in Cancer: Recent Advances and Future Directions

On ATG4B as Drug Target for Treatment of Solid Tumours—The Knowns and the Unknowns

Overexpression of PPT2 Represses the Clear Cell Renal Cell Carcinoma Progression by Reducing Epithelial-to-mesenchymal Transition

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