Rab5C enhances resistance to ionizing radiation in rectal cancer

Author(s):Show less -

Baptisteila, Antuani Rafael ^{[1, 2]} ; Landemberger, Michele Christine ^{[1, 2]} ; Salles Dia, Marcos Vinicios ^{[1, 2]} ; Giudic, Fernanda Salgueiredo ^{[1, 2]} ; Rodrigues, Bruna Roz ^{[1, 2]} ; Combas Eufrazio da Silv, Petrus Paulo ^[3] ; Cassinela, Edson Kuatelela ^{[1, 2]} ; Lacerda, Tonielli Cristina ^{[1, 2]} ; Marchi, Fabio Albuquerque ^{[1, 2]} ; Paes Leme, Adriana Franco ^[4] ; Begnami, Maria Dirlei ^{[1, 5]} ; Aguiar Jr, Samuel ; Martins, Ilma Regina ^{[6, 7]}

Affiliation

^[1] INCITO CNPq MCT FAPESP CAPES, Natl Inst Sci & Technol Oncogen, Sao Paulo - Brazil

^[2] ACCamargo Canc Ctr, Int Res Ctr, Rua Tagua 440, BR-01508010 Sao Paulo, SP - Brazil

^[3] ACCamargo Canc Ctr, Dept Med Phys, Sao Paulo - Brazil

^[4] Brazilian Biosci Natl Lab LNBio, Campinas, SP - Brazil

^[5] ACCamargo Canc Ctr, Dept Anat Pathol, Sao Paulo - Brazil

^[6] Aguiar Jr, Jr., Samuel, ACCamargo Canc Ctr, Int Res Ctr, Rua Tagua 440, BR-01508010 Sao Paulo, SP - Brazil

^[7] Aguiar Jr, Jr., Samuel, INCITO CNPq MCT FAPESP CAPES, Natl Inst Sci & Technol Oncogen, Sao Paulo - Brazil

• Document type: Journal article
• Source: JOURNAL OF MOLECULAR MEDICINE-JMM; v. 97, n. 6, p. 855-869, JUN 2019.
• Web of Science Citations: 0

Abstract

Rectal cancer represents one third of the colorectal cancers that are diagnosed. Neoadjuvant chemoradiation is a well-established protocol for rectal cancer treatment reducing the risk of local recurrence. However, a pathologic complete response is only achieved in 10-40% of cases and the mechanisms associated with resistance are poorly understood. To identify potential targets for preventing therapy resistance, a proteomic analysis of biopsy specimens collected from stage II and III rectal adenocarcinoma patients before neoadjuvant treatment was performed and compared with residual tumor tissues removed by surgery after neoadjuvant therapy. Three proteins, Ku70, Ku80, and Rab5C, exhibited a significant increase in expression after chemoradiation. To better understand the role of these proteins in therapy resistance, a rectal adenocarcinoma cell line was irradiated to generate a radiotherapy-resistant lineage. These cells overexpressed the same three proteins identified in the tissue samples. Furthermore, radiotherapy resistance in this in vitro model was found to involve modulation of epidermal growth factor receptor (EGFR) internalization by Rab5C in response to irradiation, affecting expression of the DNA repair proteins, Ku70 and Ku80, and cell resistance. Taken together, these findings indicate that EGFR and Rab5C are potential targets for the sensitization of rectal cancer cells and they should be further investigated.Key messages center dot Rab5C orchestrates a mechanism of radioresistance in rectal adenocarcinoma cell.center dot Rab5C modulates EGFR internalization and its relocalization to the nucleus.center dot In the nucleus, EGFR can modulate the expression of the DNA repair proteins, Ku70 and Ku80.center dot Rab5C, Ku70, and Ku80 are overexpressed in tumor tissues that contain tumor cells that are resistant to chemoradiation treatment. (AU)

• FAPESP's process: 10/19200-1 - Identification of mechanisms of protein STI1/Hop secretion
• Grantee: Marcos Vinicios Salles Dias
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 09/14027-2 - Mechanisms associated with the function of prion protein and its ligand STI1/Hop: therapeutic approaches
• Grantee: Vilma Regina Martins
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/04913-0 - Identification and characterization of the extracellular vesicles secreted by rectal cancer and their relation with the response to neoadjuvant treatment
• Grantee: Antuani Rafael Baptistella
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 11/18718-0 - The role of PrPc-HOP complex in colon tumors
• Grantee: Tonielli Cristina Sousa de Lacerda
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)