title: L-Ascorbic acid can abrogate SVCT-2-dependent cetuximab resistance mediated by mutant KRAS in human colon cancer cells.
abstract: Colon cancer patients with mutant KRAS are resistant to cetuximab, an antibody directed against the epidermal growth factor receptor, which is an effective clinical therapy for patients with wild-type KRAS. Numerous combinatorial therapies have been tested to overcome the resistance to cetuximab. However, no combinations have been found that can be used as effective therapeutic strategies. In this study, we demonstrate that L-ascorbic acid partners with cetuximab to induce killing effects, which are influenced by sodium-dependent vitamin C transporter 2 (SVCT-2) in human colon cancer cells with a mutant KRAS. L-Ascorbic acid treatment of human colon cancer cells that express a mutant KRAS differentially and synergistically induced cell death with cetuximab in a SVCT-2-dependent manner. The ectopic expression of SVCT-2 induced sensitivity to L-ascorbic acid treatment in human colon cancer cells that do not express SVCT-2, whereas the knockdown of endogenous SVCT-2 induced resistance to L-ascorbic acid treatment in SVCT-2-positive cells. Moreover, tumor regression via the administration of L-ascorbic acid and cetuximab in mice bearing tumor cell xenografts corresponded to SVCT-2 protein levels. Interestingly, cell death induced by the combination of L-ascorbic acid and cetuximab resulted in both apoptotic and necrotic cell death. These cell death mechanisms were related to a disruption of the ERK pathway and were represented by the impaired activation of RAFs and the activation of the ASK-1-p38 pathway. Taken together, these results suggest that resistance to cetuximab in human colon cancer patients with a mutant KRAS can be bypassed by L-ascorbic acid in an SVCT-2-dependent manner. Furthermore, SVCT-2 in mutant KRAS colon cancer may act as a potent marker for potentiating L-ascorbic acid co-treatment with cetuximab.
authors.affiliation: Innovative Cancer Research, Asan Institute for Life Science, Republic of Korea; Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympicro-43gil, Songpa-gu, Seoul, Republic of Korea.
authors.forename: Soo-A
authors.initials: SA
authors.lastname: Jung
authors.affiliation: Innovative Cancer Research, Asan Institute for Life Science, Republic of Korea; Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympicro-43gil, Songpa-gu, Seoul, Republic of Korea.
authors.forename: Dae-Hee
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Innovative Cancer Research, Asan Institute for Life Science, Republic of Korea; Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympicro-43gil, Songpa-gu, Seoul, Republic of Korea.
authors.forename: Jai-Hee
authors.initials: JH
authors.lastname: Moon
authors.affiliation: Innovative Cancer Research, Asan Institute for Life Science, Republic of Korea; Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympicro-43gil, Songpa-gu, Seoul, Republic of Korea.
authors.forename: Seung-Woo
authors.initials: SW
authors.lastname: Hong
authors.affiliation: Innovative Cancer Research, Asan Institute for Life Science, Republic of Korea; Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympicro-43gil, Songpa-gu, Seoul, Republic of Korea.
authors.forename: Jae-Sik
authors.initials: JS
authors.lastname: Shin
authors.affiliation: Innovative Cancer Research, Asan Institute for Life Science, Republic of Korea; Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympicro-43gil, Songpa-gu, Seoul, Republic of Korea.
authors.forename: Ih Yeon
authors.initials: IY
authors.lastname: Hwang
authors.affiliation: Innovative Cancer Research, Asan Institute for Life Science, Republic of Korea; Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympicro-43gil, Songpa-gu, Seoul, Republic of Korea.
authors.forename: Yu Jin
authors.initials: YJ
authors.lastname: Shin
authors.affiliation: Innovative Cancer Research, Asan Institute for Life Science, Republic of Korea; Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympicro-43gil, Songpa-gu, Seoul, Republic of Korea.
authors.forename: Jeong Hee
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Innovative Cancer Research, Asan Institute for Life Science, Republic of Korea; Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympicro-43gil, Songpa-gu, Seoul, Republic of Korea.
authors.forename: Eun-Yeung
authors.initials: EY
authors.lastname: Gong
authors.affiliation: Innovative Cancer Research, Asan Institute for Life Science, Republic of Korea; Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympicro-43gil, Songpa-gu, Seoul, Republic of Korea.
authors.forename: Seung-Mi
authors.initials: SM
authors.lastname: Kim
authors.affiliation: Innovative Cancer Research, Asan Institute for Life Science, Republic of Korea; Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympicro-43gil, Songpa-gu, Seoul, Republic of Korea.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Lee
authors.affiliation: Innovative Cancer Research, Asan Institute for Life Science, Republic of Korea; Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympicro-43gil, Songpa-gu, Seoul, Republic of Korea.
authors.forename: Seul
authors.initials: S
authors.lastname: Lee
authors.affiliation: Innovative Cancer Research, Asan Institute for Life Science, Republic of Korea; Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympicro-43gil, Songpa-gu, Seoul, Republic of Korea.
authors.forename: Jeong Eun
authors.initials: JE
authors.lastname: Kim
authors.affiliation: Innovative Cancer Research, Asan Institute for Life Science, Republic of Korea; Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympicro-43gil, Songpa-gu, Seoul, Republic of Korea.
authors.forename: Kyu-Pyo
authors.initials: KP
authors.lastname: Kim
authors.affiliation: Innovative Cancer Research, Asan Institute for Life Science, Republic of Korea; Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympicro-43gil, Songpa-gu, Seoul, Republic of Korea.
authors.forename: Yong Sang
authors.initials: YS
authors.lastname: Hong
authors.affiliation: Innovative Cancer Research, Asan Institute for Life Science, Republic of Korea; Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympicro-43gil, Songpa-gu, Seoul, Republic of Korea.
authors.forename: Jung Shin
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Innovative Cancer Research, Asan Institute for Life Science, Republic of Korea; Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympicro-43gil, Songpa-gu, Seoul, Republic of Korea; Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympicro-43gil, Songpa-gu, Seoul, Republic of Korea. Electronic address: inno183@amc.seoul.kr.
authors.forename: Dong-Hoon
authors.initials: DH
authors.lastname: Jin
authors.affiliation: Innovative Cancer Research, Asan Institute for Life Science, Republic of Korea; Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympicro-43gil, Songpa-gu, Seoul, Republic of Korea. Electronic address: twkimmd@amc.seoul.kr.
authors.forename: TaeWon
authors.initials: T
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Tumor Immunity Medical Research Center, Seoul National University College of Medicine, Seoul 110-744, Republic of Korea.
authors.forename: Wang Jae
authors.initials: WJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab / Q000008:administration & dosage; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D060347:Sodium-Coupled Vitamin C Transporters / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: C117307:KRAS protein, human; D060347:Sodium-Coupled Vitamin C Transporters; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D001205:Ascorbic Acid; D000068818:Cetuximab
keywords: Cell death; Cetuximab; L-ascorbic acid; Mutant K-Ras colon cancer; SVCT-2