Suhee Kim1,2, Sun Hee Ahn1, Hee-Young Yang1, Jin-Sil Lee1, Hyang-Gi Choi1,2, Young-Kyu Park3, Tae-Hoon Lee1,2. 1. a Department of Oral Biochemistry , Dental Science Research Institute, Medical Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University , Gwangju , Republic of Korea. 2. b Department of Molecular Medicine (BK21plus) , Chonnam National University Graduate School , Gwangju , Republic of Korea. 3. c Department of Surgery , Chonnam National University Hwasun Hospital , Hwasun , Republic of Korea.
Abstract
OBJECTIVES: In tissue samples from patients with colorectal cancer (CRC), oxidation of C420 and C457 of plakoglobin (Pg) within tumor tissue was identified by proteomic analysis. The aim of this study was to identify the roles of Pg C420 and C457. METHODS: Human CRC tissues, CRC and breast cancer cells, and normal mouse colon were prepared to validate Pg oxidation. MC38 cells were co-transfected with E-cadherin plus wild type (WT) or mutant (C420S or C457S) Pg to evaluate protein interactions and cellular localization, proliferation, and migration. RESULTS: Pg was more oxidized in stage III CRC tumor tissue than in non-tumor tissue. Similar oxidation of Pg was elicited by H2O2 treatment in normal colon and cancer cells. C457S Pg exhibited diminished binding to E-cadherin and α-catenin, and reduced the assembly of E-cadherin-α-/β-catenin complexes. Correspondingly, immunofluorescent analysis of Pg cellular localization suggested impaired binding of C457S Pg to membranes. Cell migration and proliferation were also suppressed in C457S-expressing cells. DISCUSSION: Pg appears to be redox-sensitive in cancer, and the C457 modification may impair cell migration and proliferation by affecting its interaction with the E-cadherin/catenin axis. Our findings suggest that redox-sensitive cysteines of Pg may be the targets for CRC therapy.
OBJECTIVES: In tissue samples from patients with colorectal cancer (CRC), oxidation of C420 and C457 of plakoglobin (Pg) within tumor tissue was identified by proteomic analysis. The aim of this study was to identify the roles of Pg C420 and C457. METHODS:Human CRC tissues, CRC and breast cancer cells, and normal mousecolon were prepared to validate Pg oxidation. MC38 cells were co-transfected with E-cadherin plus wild type (WT) or mutant (C420S or C457S) Pg to evaluate protein interactions and cellular localization, proliferation, and migration. RESULTS: Pg was more oxidized in stage III CRC tumor tissue than in non-tumor tissue. Similar oxidation of Pg was elicited by H2O2 treatment in normal colon and cancer cells. C457S Pg exhibited diminished binding to E-cadherin and α-catenin, and reduced the assembly of E-cadherin-α-/β-catenin complexes. Correspondingly, immunofluorescent analysis of Pg cellular localization suggested impaired binding of C457S Pg to membranes. Cell migration and proliferation were also suppressed in C457S-expressing cells. DISCUSSION: Pg appears to be redox-sensitive in cancer, and the C457 modification may impair cell migration and proliferation by affecting its interaction with the E-cadherin/catenin axis. Our findings suggest that redox-sensitive cysteines of Pg may be the targets for CRC therapy.
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