Epidermal growth factor receptor (EGFR) is overexpressed in several epithelial malignancies, including head and neck squamous cell carcinoma (HNSCC), which exhibits EGFR overexpression in up to 90% of tumors. EGFR ligands such as transforming growth factor alpha are also overexpressed in HNSCC. EGFR plays a critical role in HNSCC growth, invasion, metastasis and angiogenesis. However, EGFR inhibitors as monotherapy have yielded only modest clinical outcomes. Potential mechanisms for lack of response to EGFR inhibition in HNSCC include constitutive activation of signaling pathways independent of EGFR, as well as genetic aberrations causing dysregulation of the cell cycle. EGFR-directed therapy may be optimized by identifying and selecting those HNSCC patients most likely to benefit from EGFR inhibition. Resistance to EGFR inhibition may be circumvented by combination therapy employing EGFR inhibitors together with other treatment modalities.
The role of Src-family kinases (SFKs) in non-small cell lung cancer (NSCLC) has not been fully defined. Here we addressed this question by examining SFK phosphorylation in NSCLC biopsy samples and using genetic and pharmacological approaches to inhibit SFK expression and activity in cultured NSCLC cells. Immunohistochemical analysis of NSCLC biopsy samples using a Tyr416 phosphorylation-specific, pan-SFK antibody revealed staining in 123 (33%) of 370 tumors. Because c-Src is known to be both an upstream activator and downstream mediator of epidermal growth factor receptor (EGFR), we next investigated SFK phosphorylation in a panel of NSCLC cell lines, including ones that depend on EGFR for survival. The EGFR-dependent NSCLC cell lines HCC827 and H3255 had increased phosphorylation of SFKs, and treatment of these cells with an SFK inhibitor (PP1 or SKI-606) induced apoptosis. PP1 decreased phosphorylation of EGFR, ErbB2, and ErbB3 and strikingly enhanced apoptosis by gefitinib, an EGFR inhibitor. HCC827 cells transfected with c-Src short hairpin RNA exhibited diminished phosphorylation of EGFR and ErbB2 and decreased sensitivity to apoptosis by PP1 or gefitinib. We conclude that SFKs are activated in NSCLC biopsy samples, promote the survival of EGFR-dependent NSCLC cells, and should be investigated as therapeutic targets in
Recent findings in tumor biopsies from lung adenocarcinoma patients suggest that somatic mutations in the genes encoding epidermal growth factor receptor (EGFR) and Kirsten ras (KRAS) confer sensitivity and resistance, respectively, to EGFR inhibition. Here, we provide evidence that these genetic mutations are not sufficient to modulate the biological response of lung adenocarcinoma cells to EGFR inhibition. We found high expression of ErbB family members, ErbB ligands, or both in three models that were sensitive to EGFR inhibition, including alveolar epithelial neoplastic lesions in mice that develop lung adenocarcinoma by oncogenic KRAS, human lung adenocarcinoma cell lines, and tumor biopsies from lung adenocarcinoma patients. Thus, lung adenocarcinoma cells that depend on EGFR for survival constitutively activate the receptor through a combination of genetic mutations and overexpression of EGFR dimeric partners and their ligands. (Cancer Res 2005; 65(24): 11478-85)
Retinoic acid (RA) is the ligand for nuclear RA receptors (RARs and RXRs) and is crucial for normal epithelial cell growth and differentiation. During malignant transformation, human bronchial epithelial cells acquire a block in retinoid signaling caused in part by a transcriptional defect in RARs. Here, we show that activation of c-Jun N-terminal kinase (JNK) contributes to RAR dysfunction by phosphorylating RAR␣ and inducing degradation through the ubiquitin-proteasomal pathway. Analysis of RAR␣ mutants and phosphopeptide mapping revealed that RAR␣ residues Thr181, Ser445, and Ser461 are phosphorylated by JNK. Mutation of these residues to alanines prevented efficient ubiquitination of RAR␣ and increased the stability of the protein. We investigated the importance of RAR␣ phosphorylation by JNK as a mediator of retinoid resistance in lung cancer. Mice that develop lung cancer from activation of a latent K-ras oncogene had high intratumoral JNK activity and low RAR␣ levels and were resistant to treatment with an RAR ligand. JNK inhibition in a human lung cancer cell line enhanced RAR␣ levels, ligand-induced activity of RXR-RAR dimers, and growth inhibition by RA. These findings point to JNK as a key mediator of aberrant retinoid signaling in lung cancer cells.Retinoids (vitamin A and its retinoic acid [RA] derivatives) mediate their biologic effects through two families of nuclear receptors, the RA receptors (RAR␣, -, and -␥) and the retinoid X receptors (RXR␣, -, and -␥) (50). The stereoisomers all-trans RA and 9-cis RA are ligands for RARs, whereas RXRs can bind only to 9-cis RA. These receptors function as dimers (RXR-RAR heterodimers and RXR homodimers) that bind to retinoic acid response elements (RAREs) in gene promoters (49). Because they bind to distinct RAREs, RXR-RAR heterodimers and RXR homodimers activate the transcription of distinct sets of target genes (49).In the absence of ligand, RXR-RAR heterodimers associate with a multiprotein complex containing transcriptional corepressors that induce histone deacetylation, chromatin condensation, and transcriptional suppression (52). Ligand binding causes the receptors to dissociate from corepressors and then associate with coactivators that have histone acetyltransferase activity and induce local chromatin decondensation, recruitment of the RNA polymerase II holoenzyme, and activation of target gene transcription (51, 70). Other members of the nuclear receptor family, including those activated by vitamin D, thyroid hormone, estrogen, and progesterone, share this mechanism of activation. In addition to activating these nuclear receptors, ligand also mediates receptor destruction, in that ligand binding causes receptor ubiquitination and subsequently proteolysis through the proteasomal complex (14). Thus, the ligand tightly regulates nuclear receptor signaling through its effects on receptor function and abundance.Ubiquitination of nuclear receptors requires ligand binding. Receptor conformational changes induced by ligand are recognized by the ubiquitin...
p38 mitogen-activated protein kinase (MAPK) is activated by norepinephrine (NE) in the vasculature and is implicated in vascular smooth muscle hypertrophy, contraction, and cell migration. NE promotes influx of Ca 2ϩ and activates cytosolic phospholipase A 2 (cPLA 2 ) in vascular smooth muscle cells (VSMC). The purpose of this study was to determine the contribution of cPLA 2 -generated arachidonic acid (AA) and its metabolites to the activation of p38 MAPK measured by its phosphorylation, in response to NE in rabbit VSMC. NE-induced p38 MAPK activation was found to be mediated through the stimulation of ␣-1 and ␣-2 adrenergic receptors, was dependent on extracellular Ca 2ϩ , and was attenuated by an inhibitor of cPLA 2 (pyrrolidine-1). Moreover, the cPLA 2 product, AA, activated p38 MAPK in VSMC. p38 MAPK activation elicited by NE was decreased significantly by the lipoxygenase (LO) inhibitor baicalein, and to a lesser extent by the cytochrome P450 inhibitor 17-octadecynoic acid, but was not affected by the cyclooxygenase inhibitor indomethacin. The LO metabolites of AA, namely 5(S)-hydroxyeicosatetraenoic acid (HETE), 12(S)-HETE, and 15(S)-HETE and the cytochrome P450 metabolite 20-HETE, activated p38 MAPK. NE-induced p38 MAPK stimulation was found to be independent of phospholipase D (PLD) activation in rabbit VSMC. Transactivation of the epidermal growth factor receptor (EGFR) by NE also did not contribute to p38 MAPK activation. These data suggest that cPLA 2 -generated AA and its LO metabolites mediate NE-induced p38 MAPK stimulation in rabbit VSMC by a mechanism that is independent of PLD and EGFR activation.
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