A CD44 survival pathway triggers chemoresistance via lyn kinase and phosphoinositide 3-kinase/Akt in colon carcinoma cells.
A major obstacle to successful treatment of colorectal cancer is chemotherapy resistance. Enhanced expression of variant CD44 isoforms has been associated with aggressive tumor behavior, prompting the question of whether signaling from this receptor might modulate drug sensitivity. Activation of variant CD44 in colon carcinoma cell lines triggered resistance to the drug 1,3-bis(2-chloroethyl)-1-nitrosurea. Resistance was induced by monoclonal antibodies directed against epitopes independent of the hyaluronate-binding region but was not triggered by identical treatment of a carcinoma line expressing the standard CD44 isoform. We observed that variant CD44 produced activation of the src-family tyrosine kinase lyn. Moreover, overexpression of dominant-active lyn recapitulated chemoresistance via a pathway shown to involve activation of phosphoinositide 3-kinase and Akt. These results establish a novel role for CD44 in determining survival of colon carcinoma cells through lyn kinase and Akt. The ability to suppress apoptosis might play a critical role in the onset and development of colorectal malignancies.
Bates
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RC
Cancer Research Unit, Faculty of Medicine, The University of Newcastle, New South Wales 2308, Australia. rbates@caregroup.harvard.edu
Edwards
N S
NS
Burns
G F
GF
Fisher
D E
DE
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D002330:Carmustine / Q000494:pharmacology; D002470:Cell Survival / Q000502:physiology; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology / Q000473:pathology*; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D006801:Humans; D018960:Hyaluronan Receptors / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured; D019061:src-Family Kinases / Q000378:metabolism*
D018906:Antineoplastic Agents, Alkylating; D002330:Carmustine; D018960:Hyaluronan Receptors; D019869:Phosphatidylinositol 3-Kinases; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019061:src-Family Kinases; C060902:lyn protein-tyrosine kinase; C494918:AKT1 protein, human