Dual blockade of macropinocytosis and asparagine bioavailability shows synergistic anti-tumor effects on KRAS-mutant colorectal cancer. (1st December 2021)

• Record Type: Journal Article
• Authors: Hanada, Keita; Kawada, Kenji; Nishikawa, Gen; Toda, Kosuke; Maekawa, Hisatsugu; Nishikawa, Yasuyo; Masui, Hideyuki; Hirata, Wataru; Okamoto, Michio; Kiyasu, Yoshiyuki; Honma, Shusaku; Ogawa, Ryotaro; Mizuno, Rei; Itatani, Yoshiro; Miyoshi, Hiroyuki; Sasazuki, Takehiko; Shirasawa, Senji; Taketo, M. Mark; Obama, Kazutaka; Sakai, Yoshiharu
• Is Part Of: Cancer letters. Volume 522(2021)
• Page Start: 129
• Page End: 141
• Publication Date: 2021-12-01
• Subjects: KRAS mutation -- Macropinocytosis -- Asparagine synthetase -- l-asparaginase; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2021.09.023
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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 KRAS -mutant 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 KRAS -mutant 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 depletion-induced 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. Highlights: KRAS-mutant CRC cells enhance macropinocytosis under nutrient-depleted conditions. Rac1 and PIP3 (PI3K) are involved in macropinocytosis of KRAS -mutant CRC cells. Macropinocytosis is closely correlated with asparagine metabolism. Blockade of macropinocytosis and aspagaragine availability shows anti-tumor effects.