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    Many colorectal cancer (CRC) cells contain mutations in KRAS. Analyses of colorectal cancer cells with mutations in APC or CTNNB1 and KRAS identified SLC25A22, which encodes mitochondrial glutamate transporter, as a synthetic lethal gene. We investigated the functions of SLC25A22 in colorectal cancer cells with mutations in KRAS. We measured levels of SLC25A22 mRNA and protein in paired tumor and nontumor colon tissues collected from 130 patients in Hong Kong and 17 patients in China, and compared protein levels with patient survival times. Expression of SLC25A22 was knocked down in KRAS-mutant CRC cell lines (DLD1, HCT116, LOVO, SW480, SW620 and SW1116) and CRC cell lines without mutations in KRAS (CACO-2, COLO205, HT29 and SW48); cells were analyzed for colony formation, proliferation, glutaminolysis and aspartate synthesis, and apoptosis and in Matrigel and PCR array analyses. DLD1 and HCT116 cells with SLC25A22 knockdown were grown as xenograft tumors in nude mice; tumor growth and metastasis were measured. SLC25A22 was expressed ectopically in HCT116 cells, which were analyzed in vitro and grown as xenograft tumors in nude mice. Levels of SLC25A22 mRNA and protein were increased in colorectal tumor tissues, compared with matched nontumor colon tissues; increased protein levels were associated with shorter survival times of patients (P=.01). Knockdown of SLC25A22 in KRAS-mutant CRC cells reduced their proliferation, migration, and invasion in vitro, and tumor formation and metastasis in mice, compared to cells without SLC25A22 knockdown. Knockdown of SLC25A22 reduced aspartate biosynthesis, leading to apoptosis because KRAS-mutant CRC cells require glutamine. Incubation of KRAS-mutant CRC cells with knockdown of SLC25A22 with aspartate increased proliferation and reduced apoptosis, which required GOT1, indicating that oxaloacetate is required for cell survival. Decreased levels of oxaloacetate in cells with knockdown of SLC25A22 reduced regeneration of NAD+ and NADPH. Reduced NAD+ inhibited glycolysis and decreased levels of ATP, which inactivated MEK and ERK signaling via activation of AMPK. An increased ratio of NADP+ to NADPH induced oxidative stress and glutathione oxidation, which suppressed cell proliferation. Asparagine synthetase mediated synthesis of asparagine from aspartate to promote cell migration. SLC25A22 promotes proliferation and migration of CRC cells with mutations KRAS, and formation and metastasis of CRC xenograft tumors in mice. Patients with colorectal tumors that express increased levels of SLC25A22 have shorter survival times than patients whose tumors have lower levels. SLC25A22 induces intracellular synthesis of aspartate, activation of MEK and ERK signaling and reduces oxidative stress. Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.


    Chi Chun Wong, Yun Qian, Xiaona Li, Jiaying Xu, Wei Kang, Joanna H Tong, Ka-Fai To, Ye Jin, Weilin Li, Huarong Chen, Minnie Yy Go, Jian-Lin Wu, Ka Wing Cheng, Simon Sm Ng, Joseph Jy Sung, Zongwei Cai, Jun Yu. SLC25A22 Promotes Proliferation and Survival of Colorectal Cancer Cells With KRAS Mutations, and Xenograft Tumor Progression in Mice, via Intracellular Synthesis of Aspartate. Gastroenterology. 2016 Jul 20

    PMID: 27451147

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