TY - JOUR
T1 - Cross-Talk between Integrins and Oncogenes Modulates Chemosensitivity
AU - Puigvert, Jordi Carreras
AU - Huveneers, Stephan
AU - Fredriksson, Lisa
AU - op het Veld, Marieke
AU - van de Water, Bob
AU - Danen, Erik H. J.
PY - 2009
Y1 - 2009
N2 - 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 beta 1 or beta 3 integrins, in which p53 activity is suppressed, undergo G(2) 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 beta 1 integrins, whereas such sensitization is reduced when these cells are engineered to express beta 3 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 beta 1 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
AB - 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 beta 1 or beta 3 integrins, in which p53 activity is suppressed, undergo G(2) 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 beta 1 integrins, whereas such sensitization is reduced when these cells are engineered to express beta 3 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 beta 1 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
U2 - https://doi.org/10.1124/mol.108.051649
DO - https://doi.org/10.1124/mol.108.051649
M3 - Article
C2 - 19158362
SN - 0026-895X
VL - 75
SP - 947
EP - 955
JO - Molecular pharmacology
JF - Molecular pharmacology
IS - 4
ER -