Metabolic Alterations Caused by KRAS Mutations in Colorectal Cancer Contribute to Cell Adaptation to Glutamine Depletion by Upregulation of Asparagine Synthetase

Kosuke Toda, Kenji Kawada, Masayoshi Iwamoto, Susumu Inamoto, Takehiko Sasazuki, Senji Shirasawa, Suguru Hasegawa, Yoshiharu Sakai

Research output: Contribution to journalArticle

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Abstract

A number of clinical trials have shown that KRAS mutations of colorectal cancer (CRC) can predict a lack of responses to anti-epidermal growth factor receptor–based therapy. Recently, there have been several studies to elucidate metabolism reprogramming in cancer. However, it remains to be investigated how mutated KRAS can coordinate the metabolic shift to sustain CRC tumor growth. In this study, we found that KRAS mutation in CRC caused alteration in amino acid metabolism. KRAS mutation causes a marked decrease in aspartate level and an increase in asparagine level in CRC. Using several human CRC cell lines and clinical specimens of primary CRC, we demonstrated that the expression of asparagine synthetase (ASNS), an enzyme that synthesizes asparagine from aspartate, was upregulated by mutated KRAS and that ASNS expression was induced by KRAS-activated signaling pathway, in particular PI3K-AKT-mTOR pathway. Importantly, we demonstrated that KRAS-mutant CRC cells could become adaptive to glutamine depletion through asparagine biosynthesis by ASNS and that asparagine addition could rescue the inhibited growth and viability of cells grown under the glutamine-free condition in vitro. Notably, a pronounced growth suppression of KRAS-mutant CRC was observed upon ASNS knockdown in vivo. Furthermore, combination of L-asparaginase plus rapamycin markedly suppressed the growth of KRAS-mutant CRC xenografts in vivo, whereas either L-asparaginase or rapamycin alone was not effective. These results indicate ASNS might be a novel therapeutic target against CRCs with mutated KRAS.

Original languageEnglish
Pages (from-to)654-665
Number of pages12
JournalNeoplasia (United States)
Volume18
Issue number11
DOIs
Publication statusPublished - Jan 1 2016

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Aspartate-Ammonia Ligase
Glutamine
Colorectal Neoplasms
Up-Regulation
Mutation
Asparagine
Asparaginase
Sirolimus
Growth
Aspartic Acid
Phosphatidylinositol 3-Kinases
Epidermal Growth Factor
Heterografts
Cell Survival

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

Metabolic Alterations Caused by KRAS Mutations in Colorectal Cancer Contribute to Cell Adaptation to Glutamine Depletion by Upregulation of Asparagine Synthetase. / Toda, Kosuke; Kawada, Kenji; Iwamoto, Masayoshi; Inamoto, Susumu; Sasazuki, Takehiko; Shirasawa, Senji; Hasegawa, Suguru; Sakai, Yoshiharu.

In: Neoplasia (United States), Vol. 18, No. 11, 01.01.2016, p. 654-665.

Research output: Contribution to journalArticle

Toda, Kosuke ; Kawada, Kenji ; Iwamoto, Masayoshi ; Inamoto, Susumu ; Sasazuki, Takehiko ; Shirasawa, Senji ; Hasegawa, Suguru ; Sakai, Yoshiharu. / Metabolic Alterations Caused by KRAS Mutations in Colorectal Cancer Contribute to Cell Adaptation to Glutamine Depletion by Upregulation of Asparagine Synthetase. In: Neoplasia (United States). 2016 ; Vol. 18, No. 11. pp. 654-665.
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abstract = "A number of clinical trials have shown that KRAS mutations of colorectal cancer (CRC) can predict a lack of responses to anti-epidermal growth factor receptor–based therapy. Recently, there have been several studies to elucidate metabolism reprogramming in cancer. However, it remains to be investigated how mutated KRAS can coordinate the metabolic shift to sustain CRC tumor growth. In this study, we found that KRAS mutation in CRC caused alteration in amino acid metabolism. KRAS mutation causes a marked decrease in aspartate level and an increase in asparagine level in CRC. Using several human CRC cell lines and clinical specimens of primary CRC, we demonstrated that the expression of asparagine synthetase (ASNS), an enzyme that synthesizes asparagine from aspartate, was upregulated by mutated KRAS and that ASNS expression was induced by KRAS-activated signaling pathway, in particular PI3K-AKT-mTOR pathway. Importantly, we demonstrated that KRAS-mutant CRC cells could become adaptive to glutamine depletion through asparagine biosynthesis by ASNS and that asparagine addition could rescue the inhibited growth and viability of cells grown under the glutamine-free condition in vitro. Notably, a pronounced growth suppression of KRAS-mutant CRC was observed upon ASNS knockdown in vivo. Furthermore, combination of L-asparaginase plus rapamycin markedly suppressed the growth of KRAS-mutant CRC xenografts in vivo, whereas either L-asparaginase or rapamycin alone was not effective. These results indicate ASNS might be a novel therapeutic target against CRCs with mutated KRAS.",
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