Cbl-b enhances sensitivity to 5-fluorouracil via EGFR- and mitochondria-mediated pathways in gastric cancer cells

Int J Mol Sci. 2013 Dec 16;14(12):24399-411. doi: 10.3390/ijms141224399.

Abstract

5-Fluorouracil (5-FU) is an essential component of anticancer chemotherapy against gastric cancer. However, the response rate of single drug is still limited. The ubiquitin ligase Cbl-b is a negative regulator of growth factor receptor signaling and is involved in the suppression of cancer cell proliferation. However, whether Cbl-b could affect 5-FU sensitivity remains unclear. The present study showed that Cbl-b knockdown caused higher proliferation concomitant with the decrease of apoptosis induced by 5-FU treatment in gastric cancer cell. Further mechanism investigation demonstrated that Cbl-b knockdown caused significant increase of phosphorylation of EGFR, ERK and Akt, decrease of mitochondrial membrane potential, and increase of expression ratio of Bcl-2/Bax. These results suggest that Cbl-b enhances sensitivity to 5-FU via EGFR- and mitochondria-mediated pathways in gastric cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fluorouracil / toxicity*
  • Humans
  • Mitochondria / metabolism*
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Proto-Oncogene Proteins c-cbl / antagonists & inhibitors
  • Proto-Oncogene Proteins c-cbl / genetics
  • Proto-Oncogene Proteins c-cbl / metabolism*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Signal Transduction / drug effects
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / pathology
  • bcl-2-Associated X Protein / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Small Interfering
  • bcl-2-Associated X Protein
  • CBLB protein, human
  • Proto-Oncogene Proteins c-cbl
  • EGFR protein, human
  • ErbB Receptors
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Fluorouracil