TY - JOUR
T1 - Autophagic reliance promotes metabolic reprogramming in oncogenic KRAS-driven tumorigenesis
AU - Lin, H. Helen
AU - Chung, Yiyin
AU - Cheng, Chun Ting
AU - Ouyang, Ching
AU - Fu, Yong
AU - Kuo, Ching Ying
AU - Chi, Kevin K.
AU - Sadeghi, Maryam
AU - Chu, Peiguo
AU - Kung, Hsing Jien
AU - Li, Chien Feng
AU - Limesand, Kirsten H.
AU - Ann, David K.
PY - 2018/9/2
Y1 - 2018/9/2
N2 - Defects in basal autophagy limit the nutrient supply from recycling of intracellular constituents. Despite our understanding of the prosurvival role of macroautophagy/autophagy, how nutrient deprivation, caused by compromised autophagy, affects oncogenic KRAS-driven tumor progression is poorly understood. Here, we demonstrate that conditional impairment of the autophagy gene Atg5 (atg5-KO) extends the survival of KRASG12V-driven tumor-bearing mice by 38%. atg5-KO tumors spread more slowly during late tumorigenesis, despite a faster onset. atg5-KO tumor cells displayed reduced mitochondrial function and increased mitochondrial fragmentation. Metabolite profiles indicated a deficiency in the nonessential amino acid asparagine despite a compensatory overexpression of ASNS (asparagine synthetase), key enzyme for de novo asparagine synthesis. Inhibition of either autophagy or ASNS reduced KRASG12V-driven tumor cell proliferation, migration, and invasion, which was rescued by asparagine supplementation or knockdown of MFF (mitochondrial fission factor). Finally, these observations were reflected in human cancer-derived data, linking ASNS overexpression with poor clinical outcome in multiple cancers. Together, our data document a widespread yet specific asparagine homeostasis control by autophagy and ASNS, highlighting the previously unrecognized role of autophagy in suppressing the metabolic barriers of low asparagine and excessive mitochondrial fragmentation to permit malignant KRAS-driven tumor progression.
AB - Defects in basal autophagy limit the nutrient supply from recycling of intracellular constituents. Despite our understanding of the prosurvival role of macroautophagy/autophagy, how nutrient deprivation, caused by compromised autophagy, affects oncogenic KRAS-driven tumor progression is poorly understood. Here, we demonstrate that conditional impairment of the autophagy gene Atg5 (atg5-KO) extends the survival of KRASG12V-driven tumor-bearing mice by 38%. atg5-KO tumors spread more slowly during late tumorigenesis, despite a faster onset. atg5-KO tumor cells displayed reduced mitochondrial function and increased mitochondrial fragmentation. Metabolite profiles indicated a deficiency in the nonessential amino acid asparagine despite a compensatory overexpression of ASNS (asparagine synthetase), key enzyme for de novo asparagine synthesis. Inhibition of either autophagy or ASNS reduced KRASG12V-driven tumor cell proliferation, migration, and invasion, which was rescued by asparagine supplementation or knockdown of MFF (mitochondrial fission factor). Finally, these observations were reflected in human cancer-derived data, linking ASNS overexpression with poor clinical outcome in multiple cancers. Together, our data document a widespread yet specific asparagine homeostasis control by autophagy and ASNS, highlighting the previously unrecognized role of autophagy in suppressing the metabolic barriers of low asparagine and excessive mitochondrial fragmentation to permit malignant KRAS-driven tumor progression.
KW - asparagine
KW - asparagine synthetase
KW - autophagy
KW - metabolic reprogramming
KW - MFF
KW - mitochondria
KW - oncogenic KRAS
UR - http://www.scopus.com/inward/record.url?scp=85052104291&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85052104291&partnerID=8YFLogxK
U2 - 10.1080/15548627.2018.1450708
DO - 10.1080/15548627.2018.1450708
M3 - Article
AN - SCOPUS:85052104291
VL - 14
SP - 1481
EP - 1498
JO - Autophagy
JF - Autophagy
SN - 1554-8627
IS - 9
ER -