1. Cooperation of amphiregulin and insulin-like growth factor-1 inhibits Bax- and Bad-mediated apoptosis via a protein kinase C-dependent pathway in non-small cell lung cancer cells.: Bad and Bax inactivation by AR/IGF1-PKC-dependent pathway
- Author
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Christian Brambilla, Patrick Auberger, Marie-Christine Favrot, Jean-Luc Coll, Amandine Hurbin, Laurence Dubrez-Daloz, Bernard Mari, Groupe de Recherche Sur Le Cancer du Poumon : Bases Moléculaires de la Progression Tumorale, Dépistage et Thérapie Génique, Institut Albert Bonniot-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Mort cellulaire et cancer, Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Physiopathologie de la survie et de la mort cellulaire et infection virale, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR50-Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ), Institut Albert Bonniot-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)
- Subjects
MAPK/ERK pathway ,Lung Neoplasms ,Apoptosis ,MESH : Insulin-Like Growth Factor I ,Biochemistry ,Culture Media, Serum-Free ,[ SDV.CAN ] Life Sciences [q-bio]/Cancer ,MESH : Flavonoids ,Wortmannin ,0302 clinical medicine ,MESH : 1-Phosphatidylinositol 3-Kinase ,Enzyme Inhibitors ,MESH : Isoenzymes ,0303 health sciences ,Kinase ,MESH: Culture Media, Serum-Free ,3. Good health ,Cell biology ,Calphostin C ,030220 oncology & carcinogenesis ,Intercellular Signaling Peptides and Proteins ,MESH : bcl-Associated Death Protein ,MESH : Carrier Proteins ,MAP Kinase Signaling System ,MESH: Carrier Proteins ,Naphthalenes ,Article ,03 medical and health sciences ,Bcl-2-associated X protein ,MESH: bcl-Associated Death Protein ,Humans ,MESH : Lung Neoplasms ,Molecular Biology ,Glycoproteins ,MESH: Humans ,MESH : Carcinoma, Non-Small-Cell Lung ,MESH: MAP Kinase Signaling System ,MESH : bcl-2-Associated X Protein ,MESH : Humans ,Staurosporine ,MESH : Glycoproteins ,MESH: Lung Neoplasms ,Androstadienes ,MESH: Proto-Oncogene Proteins c-bcl-2 ,chemistry ,Carrier Proteins ,MESH: Flavonoids ,MESH : Apoptosis ,MESH: Signal Transduction ,MESH : Staurosporine ,MESH: Insulin-Like Growth Factor I ,MESH : Models, Biological ,MESH : Proto-Oncogene Proteins c-bcl-2 ,MESH : Culture Media, Serum-Free ,chemistry.chemical_compound ,Carcinoma, Non-Small-Cell Lung ,Insulin-Like Growth Factor I ,Protein Kinase C ,Phosphoinositide-3 Kinase Inhibitors ,bcl-2-Associated X Protein ,MESH: Naphthalenes ,Isoenzymes ,Proto-Oncogene Proteins c-bcl-2 ,MESH: Enzyme Inhibitors ,MESH: Isoenzymes ,bcl-Associated Death Protein ,Signal Transduction ,medicine.drug ,EGF Family of Proteins ,MESH: Cell Line, Tumor ,MESH: Glycoproteins ,MESH : Androstadienes ,MESH : MAP Kinase Signaling System ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,Amphiregulin ,Models, Biological ,Cell Line, Tumor ,MESH : Naphthalenes ,medicine ,MESH: bcl-2-Associated X Protein ,Calphostin ,MESH : Protein Kinase C ,MESH: Intercellular Signaling Peptides and Proteins ,MESH : Intercellular Signaling Peptides and Proteins ,030304 developmental biology ,Flavonoids ,MESH : Signal Transduction ,MESH : Enzyme Inhibitors ,MESH : Cell Line, Tumor ,MESH: Apoptosis ,MESH: Models, Biological ,MESH: 1-Phosphatidylinositol 3-Kinase ,Cell Biology ,MESH: Protein Kinase C ,MESH: Androstadienes ,MESH: Staurosporine ,biology.protein ,MESH: Carcinoma, Non-Small-Cell Lung - Abstract
International audience; Amphiregulin (AR) and insulin-like growth factor-1 (IGF1) are growth factors known to promote non-small cell lung cancer (NSCLC) survival. We have previously published that 1) AR and IGF1, secreted by H358 NSCLC cells, cooperate to protect those cells and H322 NSCLC cells from serum-starved apoptosis; 2) H358 cells resist Bax-induced apoptosis through an inhibition of Bax conformational change. We show here that the antiapoptotic activity of the AR/IGF1 combination is specifically abolished by the PKC inhibitors calphostin C and staurosporine, but not by the MAPK and phosphatidylinositol 3-kinase inhibitors PD98059 and wortmannin, suggesting the involvement of a PKC-dependent and MAPK- and phosphatidylinositol 3-kinase-independent survival pathway. The PKCdelta inhibitor rottlerin restores apoptosis induced by serum deprivation. In addition, phosphorylation of PKCdelta and PKCzeta/lambda, but not of PKCalpha/beta(II), increases in serum-starved H358 cells and in H322 cells treated with an AR/IGF1 combination and is blocked by calphostin C. The combination of AR and IGF1 increases p90(rsk) and Bad phosphorylation as well as inhibiting the conformational change of Bax by a PKC-dependent mechanism. Finally, PKCdelta, PKCzeta, or p90(rsk) small interfering RNAs block the antiapoptotic activity of AR/IGF1 combination but have no effect on partial apoptosis inhibition observed with each factor used alone. Constitutively active PKC expression inhibits serum deprivation-induced apoptosis, whereas a catalytically inactive form of p90(rsk) restores it. Thus, AR and IGF1 cooperate to prevent apoptosis by activating a specific PKC-p90(rsk)-dependent pathway, which leads to Bad and Bax inactivation. This signaling pathway is different to that used by single factor.
- Published
- 2005
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