期刊
CANCER LETTERS
卷 522, 期 -, 页码 129-141出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2021.09.023
关键词
KRAS mutation; Macropinocytosis; Asparagine synthetase; L-asparaginase
类别
资金
- Ministry of Education, Culture, Sports, Science and Technology of Japan
Mutations in the KRAS gene are commonly found in various cancers, including colorectal cancer. Studies have shown that KRAS-mutant CRC cells enhance macropinocytosis for tumor growth under nutrient-depleted conditions, and this process is closely correlated with asparagine metabolism. Inhibition of both macropinocytosis and asparagine availability could be a promising therapeutic strategy for KRAS-mutant cancers.
Mutations of KRAS gene are found in various types of cancer, including colorectal cancer (CRC). Despite intense efforts, no pharmacological approaches are expected to be effective against KRAS-mutant cancers. Macropinocytosis is an evolutionarily conserved actin-dependent endocytic process that internalizes extracellular fluids into large vesicles called macropinosomes. Recent studies have revealed macropinocytosis's important role in metabolic adaptation to nutrient stress in cancer cells harboring KRAS mutations. Here we showed that KRASmutant CRC cells enhanced macropinocytosis for tumor growth under nutrient-depleted conditions. We also demonstrated that activation of Rac1 and phosphoinositide 3-kinase were involved in macropinocytosis of KRASmutant CRC cells. Furthermore, we found that macropinocytosis was closely correlated with asparagine metabolism. In KRAS-mutant CRC cells engineered with knockdown of asparagine synthetase, macropinocytosis was accelerated under glutamine-depleted condition, and albumin addition could restore the glutamine depletioninduced growth suppression by recovering the intracellular asparagine level. Finally, we discovered that the combination of macropinocytosis inhibition and asparagine depletion dramatically suppressed the tumor growth of KRAS-mutant CRC cells in vivo. These results indicate that dual blockade of macropinocytosis and asparagine bioavailability could be a novel therapeutic strategy for KRAS-mutant cancers.
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