HER2 signaling downregulation by trastuzumab and suppression of the PI3K/Akt pathway: An unexpected effect on TRAIL-induced apoptosis

• Published in: FEBS letters Vol. 579; no. 19; pp. 4149 - 4158
• Main Authors: Dubská, Lenka, Anděra, Ladislav, Sheard, Michael Allen
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 01.08.2005
• Subjects: Adenocarcinoma - enzymology; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal, Humanized; Apoptosis; Apoptosis - physiology; Apoptosis Regulatory Proteins; Breast cancer; Breast Neoplasms - enzymology; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Down-Regulation; Flice-inhibitory protein; FLIP; Fluorescent Antibody Technique; Genes, erbB-2; HER2/ neu; Humans; IAP; inhibitor of apoptosis protein; MAPK; MAPK/ERK kinase; MEK; Membrane Glycoproteins - physiology; mitochondrial membrane potential; mitogen-activated protein kinase; PARP; Phosphatidylinositol 3-Kinases - metabolism; phosphatidylinositol 3′ kinase; PI3K; poly ADP-ribose polymerase; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Signal Transduction; TNF; TNF-Related Apoptosis-Inducing Ligand; TRAIL; TRAIL-R; TRAIL-receptor; Trastuzumab; tumor necrosis factor; Tumor Necrosis Factor-alpha - physiology; ΔΨ m; Δ Ψ m; TRAIL; TRAIL-R; Breast cancer; PARP; MAPK; TNF; FLIP; MEK; PI3K; HER2/ neu; IAP; Trastuzumab; Apoptosis
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2005.06.047

We investigated whether HER2 downregulation by trastuzumab modulates the responsiveness of breast cancer cells to TNF-related apoptosis-inducing ligand (TRAIL). Interestingly, in contrast to increased response to TRAIL in SKBr3 cells, trastuzumab decreased the susceptibility of BT474 cells to TRAIL. This decrease was also observed after exogenous inhibition of PI3-K/Akt kinase, but not MAPK/ERK kinase (MEK)/mitogen-activated protein kinase (MAPK). In BT474 cells, but not SKBr3 cells, inhibition of the HER2/phosphatidylinositol 3′ kinase (PI3K)/Akt pathway resulted in downregulation of the pro-apoptotic receptors TRAIL-receptor 1 (TRAIL-R1) and TRAIL-R2. TRAIL-induced caspase-8 activation, Bid processing, drop of Δ Ψ m, and poly ADP-ribose polymerase (PARP) cleavage but not in caspase-9 activation, and these events were inhibited in HER2/PI3K/Akt-suppressed BT474 cells, which on the other hand exhibited downregulation of Bcl-x L and increased response to mitomycin C. We show that HER2/PI3K/Akt pathway may play a specific pro-apoptotic role in certain cell type by inducing TRAIL-R1 and -R2 expression and thereby enhancing responsiveness to TRAIL.