A unified approach to targeting the lysosome’s degradative and growth signaling roles

Vito W. Rebecca, Michael C. Nicastri, Noel McLaughlin, Colin Fennelly, Quentin McAfee, Amruta Ronghe, Michel Nofal, Chun Yan Lim, Eric Witze, Cynthia I. Chude, Gao Zhang, Gretchen M. Alicea, Shengfu Piao, Sengottuvelan Murugan, Rani Ojha, Samuel M. Levi, Zhi Wei, Julie S. Barber-Rotenberg, Maureen E. Murphy, Gordon Mills & 12 others Yiling Lu, Joshua Rabinowitz, Ronen Marmorstein, Qin Liu, Shujing Liu, Xiaowei Xu, Meenhard Herlyn, Roberto Zoncu, Donita C. Brady, David W. Speicher, Jeffrey D. Winkler, Ravi K. Amaravadi

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Lysosomes serve dual roles in cancer metabolism, executing catabolic programs (i.e., autophagy and macropinocytosis) while promoting mTORC1-dependent anabolism. Antimalarial compounds such as chloroquine or quinacrine have been used as lysosomal inhibitors, but fail to inhibit mTOR signaling. Further, the molecular target of these agents has not been identified. We report a screen of novel dimeric antimalarials that identifies dimeric quinacrines (DQ) as potent anticancer compounds, which concurrently inhibit mTOR and autophagy. Central nitrogen methylation of the DQ linker enhances lysosomal localization and potency. An in situ photoaffin-ity pulldown identified palmitoyl-protein thioesterase 1 (PPT1) as the molecular target of DQ661. PPT1 inhibition concurrently impairs mTOR and lysosomal catabolism through the rapid accumulation of palmitoylated proteins. DQ661 inhibits the in vivo tumor growth of melanoma, pancreatic cancer, and colorectal cancer mouse models and can be safely combined with chemotherapy. Thus, lysosome-directed PPT1 inhibitors represent a new approach to concurrently targeting mTORC1 and lysosomal catabolism in cancer. SIGNIFICANCE: This study identifies chemical features of dimeric compounds that increase their lysosomal specificity, and a new molecular target for these compounds, reclassifying these compounds as targeted therapies. Targeting PPT1 blocks mTOR signaling in a manner distinct from catalytic inhibitors, while concurrently inhibiting autophagy, thereby providing a new strategy for cancer therapy.

Original languageEnglish (US)
Pages (from-to)1266-1283
Number of pages18
JournalCancer Discovery
Volume7
Issue number11
DOIs
StatePublished - Nov 1 2017
Externally publishedYes

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Lysosomes
Autophagy
Antimalarials
Growth
Neoplasms
Quinacrine
Chloroquine
Pancreatic Neoplasms
Methylation
Colorectal Neoplasms
Melanoma
Nitrogen
Drug Therapy
palmitoyl-protein thioesterase
Therapeutics
Proteins
mechanistic target of rapamycin complex 1

ASJC Scopus subject areas

  • Oncology

Cite this

Rebecca, V. W., Nicastri, M. C., McLaughlin, N., Fennelly, C., McAfee, Q., Ronghe, A., ... Amaravadi, R. K. (2017). A unified approach to targeting the lysosome’s degradative and growth signaling roles. Cancer Discovery, 7(11), 1266-1283. https://doi.org/10.1158/2159-8290.CD-17-0741

A unified approach to targeting the lysosome’s degradative and growth signaling roles. / Rebecca, Vito W.; Nicastri, Michael C.; McLaughlin, Noel; Fennelly, Colin; McAfee, Quentin; Ronghe, Amruta; Nofal, Michel; Lim, Chun Yan; Witze, Eric; Chude, Cynthia I.; Zhang, Gao; Alicea, Gretchen M.; Piao, Shengfu; Murugan, Sengottuvelan; Ojha, Rani; Levi, Samuel M.; Wei, Zhi; Barber-Rotenberg, Julie S.; Murphy, Maureen E.; Mills, Gordon; Lu, Yiling; Rabinowitz, Joshua; Marmorstein, Ronen; Liu, Qin; Liu, Shujing; Xu, Xiaowei; Herlyn, Meenhard; Zoncu, Roberto; Brady, Donita C.; Speicher, David W.; Winkler, Jeffrey D.; Amaravadi, Ravi K.

In: Cancer Discovery, Vol. 7, No. 11, 01.11.2017, p. 1266-1283.

Research output: Contribution to journalArticle

Rebecca, VW, Nicastri, MC, McLaughlin, N, Fennelly, C, McAfee, Q, Ronghe, A, Nofal, M, Lim, CY, Witze, E, Chude, CI, Zhang, G, Alicea, GM, Piao, S, Murugan, S, Ojha, R, Levi, SM, Wei, Z, Barber-Rotenberg, JS, Murphy, ME, Mills, G, Lu, Y, Rabinowitz, J, Marmorstein, R, Liu, Q, Liu, S, Xu, X, Herlyn, M, Zoncu, R, Brady, DC, Speicher, DW, Winkler, JD & Amaravadi, RK 2017, 'A unified approach to targeting the lysosome’s degradative and growth signaling roles', Cancer Discovery, vol. 7, no. 11, pp. 1266-1283. https://doi.org/10.1158/2159-8290.CD-17-0741
Rebecca VW, Nicastri MC, McLaughlin N, Fennelly C, McAfee Q, Ronghe A et al. A unified approach to targeting the lysosome’s degradative and growth signaling roles. Cancer Discovery. 2017 Nov 1;7(11):1266-1283. https://doi.org/10.1158/2159-8290.CD-17-0741
Rebecca, Vito W. ; Nicastri, Michael C. ; McLaughlin, Noel ; Fennelly, Colin ; McAfee, Quentin ; Ronghe, Amruta ; Nofal, Michel ; Lim, Chun Yan ; Witze, Eric ; Chude, Cynthia I. ; Zhang, Gao ; Alicea, Gretchen M. ; Piao, Shengfu ; Murugan, Sengottuvelan ; Ojha, Rani ; Levi, Samuel M. ; Wei, Zhi ; Barber-Rotenberg, Julie S. ; Murphy, Maureen E. ; Mills, Gordon ; Lu, Yiling ; Rabinowitz, Joshua ; Marmorstein, Ronen ; Liu, Qin ; Liu, Shujing ; Xu, Xiaowei ; Herlyn, Meenhard ; Zoncu, Roberto ; Brady, Donita C. ; Speicher, David W. ; Winkler, Jeffrey D. ; Amaravadi, Ravi K. / A unified approach to targeting the lysosome’s degradative and growth signaling roles. In: Cancer Discovery. 2017 ; Vol. 7, No. 11. pp. 1266-1283.
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AU - Rebecca, Vito W.

AU - Nicastri, Michael C.

AU - McLaughlin, Noel

AU - Fennelly, Colin

AU - McAfee, Quentin

AU - Ronghe, Amruta

AU - Nofal, Michel

AU - Lim, Chun Yan

AU - Witze, Eric

AU - Chude, Cynthia I.

AU - Zhang, Gao

AU - Alicea, Gretchen M.

AU - Piao, Shengfu

AU - Murugan, Sengottuvelan

AU - Ojha, Rani

AU - Levi, Samuel M.

AU - Wei, Zhi

AU - Barber-Rotenberg, Julie S.

AU - Murphy, Maureen E.

AU - Mills, Gordon

AU - Lu, Yiling

AU - Rabinowitz, Joshua

AU - Marmorstein, Ronen

AU - Liu, Qin

AU - Liu, Shujing

AU - Xu, Xiaowei

AU - Herlyn, Meenhard

AU - Zoncu, Roberto

AU - Brady, Donita C.

AU - Speicher, David W.

AU - Winkler, Jeffrey D.

AU - Amaravadi, Ravi K.

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