Roles of the PI-3K and MEK Pathways in Ras-mediated Chemoresistance in Breast Cancer Cells

Overview

Journal Br J Cancer

Specialty Oncology

Date 2003 Jul 3

PMID 12838322

Citations 44

Authors

W Jin

L Wu

K Liang

B Liu

Y Lu

Z Fan

Affiliations

Soon will be listed here.

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 specific 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.

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References

Sukumar S, Carney W, Barbacid M . Independent molecular pathways in initiation and loss of hormone responsiveness of breast carcinomas. Science. 1988; 240(4851):524-6. DOI: 10.1126/science.3282307. View

Gooch J, Van den Berg C, Yee D . Insulin-like growth factor (IGF)-I rescues breast cancer cells from chemotherapy-induced cell death--proliferative and anti-apoptotic effects. Breast Cancer Res Treat. 1999; 56(1):1-10. DOI: 10.1023/a:1006208721167. View

Nooter K, Boersma A, Oostrum R, Burger H, Jochemsen A, Stoter G . Constitutive expression of the c-H-ras oncogene inhibits doxorubicin-induced apoptosis and promotes cell survival in a rhabdomyosarcoma cell line. Br J Cancer. 1995; 71(3):556-61. PMC: 2033635. DOI: 10.1038/bjc.1995.109. View

Fan Z, Lu Y, Wu X, DEBLASIO A, Koff A, Mendelsohn J . Prolonged induction of p21Cip1/WAF1/CDK2/PCNA complex by epidermal growth factor receptor activation mediates ligand-induced A431 cell growth inhibition. J Cell Biol. 1995; 131(1):235-42. PMC: 2120589. DOI: 10.1083/jcb.131.1.235. View

Datta K, Bellacosa A, Chan T, Tsichlis P . Akt is a direct target of the phosphatidylinositol 3-kinase. Activation by growth factors, v-src and v-Ha-ras, in Sf9 and mammalian cells. J Biol Chem. 1996; 271(48):30835-9. DOI: 10.1074/jbc.271.48.30835. View

Datta S, Dudek H, Tao X, Masters S, Fu H, Gotoh Y . Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997; 91(2):231-41. DOI: 10.1016/s0092-8674(00)80405-5. View

del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G . Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science. 1997; 278(5338):687-9. DOI: 10.1126/science.278.5338.687. View

Liu A, Testa J, Hamilton T, Jove R, Nicosia S, Cheng J . AKT2, a member of the protein kinase B family, is activated by growth factors, v-Ha-ras, and v-src through phosphatidylinositol 3-kinase in human ovarian epithelial cancer cells. Cancer Res. 1998; 58(14):2973-7. View

Stambolic V, Suzuki A, de la Pompa J, Brothers G, Mirtsos C, Sasaki T . Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell. 1998; 95(1):29-39. DOI: 10.1016/s0092-8674(00)81780-8. View

10.

Cardone M, Roy N, Stennicke H, Salvesen G, Franke T, Stanbridge E . Regulation of cell death protease caspase-9 by phosphorylation. Science. 1998; 282(5392):1318-21. DOI: 10.1126/science.282.5392.1318. View

11.

Du K, Montminy M . CREB is a regulatory target for the protein kinase Akt/PKB. J Biol Chem. 1998; 273(49):32377-9. DOI: 10.1074/jbc.273.49.32377. View

12.

Koo H, Kohlhagen G, McWilliams M, Jeffers M, Alvord W, Monks A . The ras oncogene-mediated sensitization of human cells to topoisomerase II inhibitor-induced apoptosis. J Natl Cancer Inst. 1999; 91(3):236-44. DOI: 10.1093/jnci/91.3.236. View

13.

Ramaswamy S, Nakamura N, Vazquez F, Batt D, Perera S, Roberts T . Regulation of G1 progression by the PTEN tumor suppressor protein is linked to inhibition of the phosphatidylinositol 3-kinase/Akt pathway. Proc Natl Acad Sci U S A. 1999; 96(5):2110-5. PMC: 26745. DOI: 10.1073/pnas.96.5.2110. View

14.

Brunet A, Bonni A, Zigmond M, Lin M, Juo P, Hu L . Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999; 96(6):857-68. DOI: 10.1016/s0092-8674(00)80595-4. View

15.

Ozes O, Mayo L, Gustin J, Pfeffer S, Pfeffer L, Donner D . NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature. 1999; 401(6748):82-5. DOI: 10.1038/43466. View

16.

Liu B, Fang M, Schmidt M, Lu Y, Mendelsohn J, Fan Z . Induction of apoptosis and activation of the caspase cascade by anti-EGF receptor monoclonal antibodies in DiFi human colon cancer cells do not involve the c-jun N-terminal kinase activity. Br J Cancer. 2000; 82(12):1991-9. PMC: 2363248. DOI: 10.1054/bjoc.2000.1201. View

17.

Viktorsson K, Heiden T, Molin M, Akusjarvi G, Linder S, Shoshan M . Increased apoptosis and increased clonogenic survival of 12V-H-ras transformed rat fibroblasts in response to cisplatin. Apoptosis. 2001; 5(4):355-67. DOI: 10.1023/a:1009639726168. View

18.

Gupta A, Bakanauskas V, Cerniglia G, Cheng Y, Bernhard E, Muschel R . The Ras radiation resistance pathway. Cancer Res. 2001; 61(10):4278-82. View

19.

Adjei A . Blocking oncogenic Ras signaling for cancer therapy. J Natl Cancer Inst. 2001; 93(14):1062-74. DOI: 10.1093/jnci/93.14.1062. View

20.

Stal O . Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients. Br J Cancer. 2002; 86(4):540-5. PMC: 2375266. DOI: 10.1038/sj.bjc.6600126. View