Rab5C enhances resistance to ionizing radiation in rectal cancer.

Autor: Baptistella AR; International Research Center, A.C.Camargo Cancer Center, Rua Taguá, 440, Liberdade, São Paulo/SP, 01508-010, Brazil.; National Institute for Science and Technology in Oncogenomics - INCITO (CNPq/MCT/FAPESP/CAPES), São Paulo, Brazil., Landemberger MC; International Research Center, A.C.Camargo Cancer Center, Rua Taguá, 440, Liberdade, São Paulo/SP, 01508-010, Brazil.; National Institute for Science and Technology in Oncogenomics - INCITO (CNPq/MCT/FAPESP/CAPES), São Paulo, Brazil., Dias MVS; International Research Center, A.C.Camargo Cancer Center, Rua Taguá, 440, Liberdade, São Paulo/SP, 01508-010, Brazil.; National Institute for Science and Technology in Oncogenomics - INCITO (CNPq/MCT/FAPESP/CAPES), São Paulo, Brazil., Giudice FS; International Research Center, A.C.Camargo Cancer Center, Rua Taguá, 440, Liberdade, São Paulo/SP, 01508-010, Brazil.; National Institute for Science and Technology in Oncogenomics - INCITO (CNPq/MCT/FAPESP/CAPES), São Paulo, Brazil., Rodrigues BR; International Research Center, A.C.Camargo Cancer Center, Rua Taguá, 440, Liberdade, São Paulo/SP, 01508-010, Brazil.; National Institute for Science and Technology in Oncogenomics - INCITO (CNPq/MCT/FAPESP/CAPES), São Paulo, Brazil., da Silva PPCE; Department of Medical Physics, A.C.Camargo Cancer Center, São Paulo, Brazil., Cassinela EK; International Research Center, A.C.Camargo Cancer Center, Rua Taguá, 440, Liberdade, São Paulo/SP, 01508-010, Brazil.; National Institute for Science and Technology in Oncogenomics - INCITO (CNPq/MCT/FAPESP/CAPES), São Paulo, Brazil., Lacerda TC; International Research Center, A.C.Camargo Cancer Center, Rua Taguá, 440, Liberdade, São Paulo/SP, 01508-010, Brazil.; National Institute for Science and Technology in Oncogenomics - INCITO (CNPq/MCT/FAPESP/CAPES), São Paulo, Brazil., Marchi FA; International Research Center, A.C.Camargo Cancer Center, Rua Taguá, 440, Liberdade, São Paulo/SP, 01508-010, Brazil.; National Institute for Science and Technology in Oncogenomics - INCITO (CNPq/MCT/FAPESP/CAPES), São Paulo, Brazil., Leme AFP; Brazilian Biosciences National Laboratory-LNBio, Campinas, Brazil., Begnami MD; National Institute for Science and Technology in Oncogenomics - INCITO (CNPq/MCT/FAPESP/CAPES), São Paulo, Brazil.; Department of Anatomic Pathology, A.C.Camargo Cancer Center, São Paulo, Brazil., Aguiar S Jr; International Research Center, A.C.Camargo Cancer Center, Rua Taguá, 440, Liberdade, São Paulo/SP, 01508-010, Brazil. samuel.aguiar@accamargo.org.br.; National Institute for Science and Technology in Oncogenomics - INCITO (CNPq/MCT/FAPESP/CAPES), São Paulo, Brazil. samuel.aguiar@accamargo.org.br.; Department of Pelvic Surgery, A.C.Camargo Cancer Center, São Paulo, Brazil. samuel.aguiar@accamargo.org.br., Martins VR; International Research Center, A.C.Camargo Cancer Center, Rua Taguá, 440, Liberdade, São Paulo/SP, 01508-010, Brazil. vmartins@cipe.accamargo.org.br.; National Institute for Science and Technology in Oncogenomics - INCITO (CNPq/MCT/FAPESP/CAPES), São Paulo, Brazil. vmartins@cipe.accamargo.org.br.
Jazyk: angličtina
Zdroj: Journal of molecular medicine (Berlin, Germany) [J Mol Med (Berl)] 2019 Jun; Vol. 97 (6), pp. 855-869. Date of Electronic Publication: 2019 Apr 09.
DOI: 10.1007/s00109-019-01760-6
Abstrakt: 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: • Rab5C orchestrates a mechanism of radioresistance in rectal adenocarcinoma cell. • Rab5C modulates EGFR internalization and its relocalization to the nucleus. • In the nucleus, EGFR can modulate the expression of the DNA repair proteins, Ku70 and Ku80. • Rab5C, Ku70, and Ku80 are overexpressed in tumor tissues that contain tumor cells that are resistant to chemoradiation treatment.
Databáze: MEDLINE
Externí odkaz: