ABSTRACT
Epidermal growth factor receptor (EGFR) regulates multiple signaling cascades essential for cell proliferation, growth and differentiation. Using a genetic approach, we found that Drosophila FERM and PDZ domain-containing protein tyrosine phosphatase, dPtpmeg, negatively regulates border cell migration and inhibits the EGFR/Ras/mitogen-activated protein kinase signaling pathway during wing morphogenesis. We further identified EGFR pathway substrate 15 (Eps15) as a target of dPtpmeg and its human homolog PTPN3. Eps15 is a scaffolding adaptor protein known to be involved in EGFR endocytosis and trafficking. Interestingly, PTPN3-mediated tyrosine dephosphorylation of Eps15 promotes EGFR for lipid raft-mediated endocytosis and lysosomal degradation. PTPN3 and the Eps15 tyrosine phosphorylation-deficient mutant suppress non-small-cell lung cancer cell growth and migration in vitro and reduce lung tumor xenograft growth in vivo. Moreover, depletion of PTPN3 impairs the degradation of EGFR and enhances proliferation and tumorigenicity of lung cancer cells. Taken together, these results indicate that PTPN3 may act as a tumor suppressor in lung cancer through its modulation of EGFR signaling.
Subject(s)
Carcinoma, Non-Small-Cell Lung/metabolism , Cell Movement , Cell Proliferation , ErbB Receptors/metabolism , Lung Neoplasms/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 3/metabolism , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Animals , Animals, Genetically Modified , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line , Cell Line, Tumor , Endocytosis , Female , HEK293 Cells , Humans , Immunoblotting , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Membrane Microdomains/metabolism , Mice, Inbred BALB C , Mice, Nude , Microscopy, Confocal , Mutation , Phosphorylation , Protein Tyrosine Phosphatase, Non-Receptor Type 3/genetics , RNA Interference , Transplantation, HeterologousABSTRACT
OBJECTIVE: Safety of multiple 16-week courses of imiquimod applied to large areas (>25 cm(2)) of skin with actinic keratoses. DESIGN: Subjects applied 1 to 6 packets two times per week for 16 weeks; if actinic keratoses were persistent at two months post-treatment, up to two additional courses could be administered within the 18-month study period. SETTING: Multicenter, outpatient. PARTICIPANTS: Adults with >/=4 actinic keratoses on the head, torso, and/or extremities. MEASUREMENTS: Treatment discontinuations, adverse events, lesion counts. RESULTS: Safety analyses included 551 subjects. At baseline, mean overall treatment area was 625+/-1114cm(2). Overall, the mean days on study was 467+/-157, and the mean exposure 215+/-133 packets with 155, 150, and 250 subjects receiving 1, 2, or 3 treatment courses, respectively. Of the 155 subjects (28.1%) who did not complete the study, 20 (3.6%) and 9 (1.6%) were discontinued for adverse events and local skin reactions, respectively. Adverse events related to study drug were reported by 40.5 percent of subjects. The local skin reactions rated as severe reported by the most subjects were erythema (31.4%), flaking/scaling/drying (23.8%), and scabbing/crusting (22.0%). For 525 subjects with analyzable lesion data, the mean baseline lesion count was 45.5+/-2.4. Overall reduction in target lesion count was 80.2 percent (p<0.0001, 95% CI 77.2-83.3%), with overall complete clearance rate of 36.4 percent and partial clearance rate (>/=75% reduction) of 68.6 percent. CONCLUSION: Multiple 16-week courses of imiquimod to treat actinic keratoses were well tolerated and significantly decreased lesions in subjects with extensive actinic keratoses.
ABSTRACT
BACKGROUND: Resiquimod, a toll-like receptor 7 and 8 agonist, may be effective as a topical treatment of actinic keratosis (AK). OBJECTIVES: To evaluate the effect of resiquimod gel concentration on lesion clearance. METHODS: Patients with AK lesions on the face or balding scalp were randomly assigned to resiquimod 0.01%, 0.03%, 0.06% or 0.1% gel applied once daily three times a week for 4 weeks to a contiguous 25-cm(2) area with four to eight lesions. Patients with persistent lesions received a second course after an 8-week treatment-free interval. Complete and partial lesion clearance was assessed 8 weeks after treatment for each course. RESULTS: For the 132 patients randomized, overall complete clearance rates were 77.1% (27/35), 90.3% (28/31), 78.1% (25/32) and 85.3% (29/34) and complete clearance rates after course 1 only were 40.0%, 74.2%, 56.3% and 70.6%, respectively, for the resiquimod 0.01%, 0.03%, 0.06% and 0.1% groups. During course 1, respectively 0%, 13%, 31% and 38% of patients discontinued treatment for adverse events or local skin reactions, for the resiquimod 0.01%, 0.03%, 0.06% and 0.1% groups. Possibly or probably related nonapplication site adverse events of severe intensity, including influenza-like symptoms, were reported by 0%, 3%, 13% and 12% of patients, respectively, for the resiquimod 0.01%, 0.03%, 0.06% and 0.1% groups. CONCLUSIONS: Efficacy in clearing AK lesions was similar between the resiquimod concentrations evaluated, but resiquimod 0.01% and 0.03% were better tolerated than the higher concentrations.
