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 language | English (US) |
|---|---|
| Pages (from-to) | 1266-1283 |
| Number of pages | 18 |
| Journal | Cancer Discovery |
| Volume | 7 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 1 2017 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Oncology
Cite this
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 journal › Article
}
TY - JOUR
T1 - A unified approach to targeting the lysosome’s degradative and growth signaling roles
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.
PY - 2017/11/1
Y1 - 2017/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85032959641&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85032959641&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-17-0741
DO - 10.1158/2159-8290.CD-17-0741
M3 - Article
VL - 7
SP - 1266
EP - 1283
JO - Cancer Discovery
JF - Cancer Discovery
SN - 2159-8274
IS - 11
ER -