Priority Research Papers:
Catabolic pathways regulated by mTORC1 are pivotal for survival and growth of cancer cells expressing mutant Ras
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Suhyun Sung1,*, Jungwon Choi1,* and Heesun Cheong1
1 Comparative Biomedicine Research Branch, Division of Cancer Biology, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do, Republic of Korea
* These authors have contributed equally to this work
Heesun Cheong, email:
Keywords: autophagy, macropinocytosis, mTORC1, KRas, pancreatic ductal adenocarcinoma (PDA)
Received: September 21, 2015 Accepted: November 10, 2015 Published: November 14, 2015
Oncogenic Ras stimulates macropinocytosis, a clathrin-independent endocytosis that increases the uptake of extracellular fluid. However, the functional significance of and regulatory mechanisms driving macropinocytosis in cancer cells remain largely unknown. Here, we show that extracellular macromolecules, such as albumin, internalized by Ras-expressing cells can support growth and survival under the nutrient-deprived conditions like those found in tumors. Moreover, we demonstrate that autophagy, a lysosome-mediated catabolic pathway, is required for the uptake and degradation of macropinocytic vesicles. Intracellular metabolites derived from macropinocytosis and autophagy directly influence the activity and localization of mTOR, which is ultimately responsible for the restoration of cell growth. Surprisingly, suppression of mTORC1, which typically triggers anabolic processes, facilitates macropinocytosis and thus supports cell growth and survival under the nutrient-deprived conditions. In a mouse xenograft model of pancreatic ductal adenocarcinoma, concomitant inhibition of macropinocytosis/autophagy and mTOR activity resulted in antitumor effects. These data suggest that novel anti-cancer strategies interrupting these metabolic processes and related signaling molecules may represent promising therapeutic avenues.
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