Roles of the PI-3K and MEK pathways in Ras-mediated chemoresistance in breast cancer cells

W. Jin, L. Wu, K. Liang, B. Liu, Y. Lu, Zhen Fan

Research output: Contribution to journalArticle

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Abstract

Activated Ras utilises several downstream pathways, including the mitogen-activated protein kinase (MAPK) kinase (MEK)/MAPK pathway and the phosphoinositide 3-kinase (PI-3k)/Akt pathway, to promote cell proliferation and to inhibit apoptosis. To investigate which pathway plays a major role in Ras-induced drug resistance to chemotherapeutic agents in breast cancer cells, we transfected MCF7 breast cancer cells with a constitutively active H-RasG12V and examined the toxicities of three commonly used breast cancer chemotherapeutic agents, paclitaxel, doxorubicin, and 5-fluorouracil in these cells under the conditions that PI-3K or MEK were selectively inhibited by their respective specifc inhibitors or dominant negative expression vectors. We found that Ras-mediated drug resistance is well correlated with resistance to apoptosis induced by anticancer agents in MCF7 breast cancer cells. Although inhibition of MEK/MAPK or PI-3K/Akt can each enhance the cytotoxicity of paclitaxel, doxorubicin, or 5-fluorouracil, inhibition of the PI-3K/Akt pathway seems to have a greater effect than inhibition of the MEK/MAPK pathway in reversing Ras-mediated drug resistance. Our results indicate that the PI-3K pathway may play a more important role in receptor tyrosine kinase-mediated resistance to chemotherapy and suggest that PI-3K/Akt might be a critical target molecule for anticancer intervention in breast cancer.

Original languageEnglish (US)
Pages (from-to)185-191
Number of pages7
JournalBritish journal of cancer
Volume89
Issue number1
DOIs
StatePublished - Jul 7 2003

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Mitogen-Activated Protein Kinase Kinases
Phosphatidylinositol 3-Kinases
Breast Neoplasms
Drug Resistance
Paclitaxel
Mitogen-Activated Protein Kinases
Fluorouracil
Doxorubicin
Apoptosis
MAP Kinase Kinase Kinases
1-Phosphatidylinositol 4-Kinase
MCF-7 Cells
Receptor Protein-Tyrosine Kinases
Antineoplastic Agents
Cell Proliferation
Drug Therapy

Keywords

  • Akt
  • Breast cancer
  • Drug resistance
  • MAPK
  • Ras

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Roles of the PI-3K and MEK pathways in Ras-mediated chemoresistance in breast cancer cells. / Jin, W.; Wu, L.; Liang, K.; Liu, B.; Lu, Y.; Fan, Zhen.

In: British journal of cancer, Vol. 89, No. 1, 07.07.2003, p. 185-191.

Research output: Contribution to journalArticle

Jin, W. ; Wu, L. ; Liang, K. ; Liu, B. ; Lu, Y. ; Fan, Zhen. / Roles of the PI-3K and MEK pathways in Ras-mediated chemoresistance in breast cancer cells. In: British journal of cancer. 2003 ; Vol. 89, No. 1. pp. 185-191.
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