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Transl Oncol. 2017 Oct;10(5):726-733. doi: 10.1016/j.tranon.2017.06.008. Epub 2017 Jul 19.

Inhibition of pRB Pathway Differentially Modulates Apoptosis in Esophageal Cancer Cells.

Author information

1
Biomedical Sciences Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil, 21949-590; Pharmacy Unit, State University of West Zone, Rio de Janeiro, Rio de Janeiro, Brazil. Electronic address: rossanasoletti@gmail.com.
2
Biomedical Sciences Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil, 21949-590. Electronic address: deborahbiasoli@gmail.com.
3
Biomedical Sciences Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil, 21949-590. Electronic address: nathassya.accioly@gmail.com.
4
Biomedical Sciences Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil, 21949-590. Electronic address: jmdelou@gmail.com.
5
D'Or Institute for Research and Education (IDOR), Rio de Janeiro, RJ, Brazil. Electronic address: rmmdsantos@gmail.com.
6
Pathology Department, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. Electronic address: veraachagas@gmail.com.
7
Biomedical Sciences Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil, 21949-590. Electronic address: rodrigomartins@ufrj.br.
8
Biomedical Sciences Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil, 21949-590; D'Or Institute for Research and Education (IDOR), Rio de Janeiro, RJ, Brazil. Electronic address: srehen@lance-ufrj.org.
9
Biomedical Sciences Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil, 21949-590. Electronic address: hborges@icb.ufrj.br.

Abstract

Esophageal cancer is the sixth most common cause of cancer-related death worldwide. Current chemotherapy regimens include a combination of 5-fluorouracil (5-FU) and cisplatin, but more efficient therapy strategies are needed to increase 5-year survival. Alterations in the signaling pathway of the tumor suppressor gene Rb-1, which encodes a phosphoprotein (pRB) that negatively regulates the G1/S transition of the cell cycle, are present in 70% of all tumors, but its role in esophageal cancer is still unclear. Most of these are alterations leading to up-regulation of the activity of cyclin-dependent kinases (CDKs) to phosphorylate pRB, which suggests that keeping the wild type pRB phosphorylated might be advantageous. Besides proliferation, pRB also regulates apoptosis induced by tumor necrosis factor-alpha (TNF-α) and DNA-damage. We investigated the status of phosphorylation of pRB along esophageal tumorigenesis stages, as well as whether hyperphosphorylation of pRB could suppress apoptosis induced by cisplatin, 5-FU, or TNF-α in esophageal cancer cells. pRB phosphorylation increased progressively from normal esophageal tissue to metaplasia and adenocarcinoma, suggesting that pRB phosphorylation increases along esophageal tumor stages. When RB-1 was knocked down or CDK inhibitors reduced the levels of phosphorylated pRB, opposite apoptotic effects were observed, depending on the combination of drugs tested: whereas TNF-α- and cisplatin-induced apoptosis increased, 5-FU-induced apoptosis decreased. Taken together, these data suggest that pRB plays a role in esophageal adenocarcinoma and that, depending on the type of anti-cancer treatment, combining CDK inhibitors and chemotherapy has the potential to increase the sensitivity of esophageal cancer cells to cell death.

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