RT Journal Article
SR Electronic
T1 Cross-Talk between Integrins and Oncogenes Modulates Chemosensitivity
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 947
OP 955
DO 10.1124/mol.108.051649
VO 75
IS 4
A1 Jordi Carreras Puigvert
A1 Stephan Huveneers
A1 Lisa Fredriksson
A1 Marieke op het Veld
A1 Bob van de Water
A1 Erik H. J. Danen
YR 2009
UL http://molpharm.aspetjournals.org/content/75/4/947.abstract
AB Chemotherapy often relies on cancer cell death resulting from DNA damage. The p53 tumor suppressor pathway that is an important player in DNA damage response is frequently inactivated in cancer. Genotoxicants also activate DNA damage-independent stress pathways and activity of oncogenic signaling and adhesive interactions with the cancer microenvironment can have a strong impact on chemosensitivity. Here, we have investigated how two different oncogenes modulate the response to genotoxicants in the context of two classes of integrin adhesion receptors. Epithelial cells expressing either β1 or β3 integrins, in which p53 activity is suppressed, undergo G2 arrest but show little apoptosis after treatment with cisplatin or other genotoxicants. The apoptotic response is strongly enhanced by the c-Src[Y530F] oncogene in cells expressing β1 integrins, whereas such sensitization is reduced when these cells are engineered to express β3 integrins instead. The H-Ras[G12V] oncogene fails to sensitize, regardless of the integrin expression profile. The enhanced sensitivity induced by c-Src[Y530F] in the context of β1 integrins does not rely on p53-mediated DNA damage signaling but instead involves increased endoplasmic reticulum stress and caspase-3 activation. Our data implicate that the expression profiles of oncogenes and integrins strongly affect the response to chemotherapeutics and may thus determine the efficacy of chemotherapy. The American Society for Pharmacology and Experimental Therapeutics