Heterogeneity in retinoic acid signaling in neuroblastomas: Role of matrix metalloproteinases in retinoic acid-induced differentiation.
Causes of retinoid resistance often observed in neuroblastomas are unknown. We studied all trans-retinoic acid (RA) signaling in neuroblastoma cells differing in N-myc levels in terms of neurite formation, expression of tissue transglutaminase, neuronal marker proteins, matrix metalloproteinases (MMPs), and activation of Rac1 and Cdc42. Poor invasiveness observed in SH-SY5Y, LA-N-5, and SMS-KCNR cells was associated with RA-induced neurite formation, Cdc42 activation and N-myc down regulation; expression of constitutively active Cdc42 down regulated N-myc expression and reduced invasion in RA-resistant SK-N-BE(2) and IMR32 cells. RA treatment for 24 h transiently increased invasion and expression of MMP9 in SH-SY5Y, LA-N-5 and MMP2 in SMS-KCNR cells. MMP inhibition prevented RA-induced neurite formation indicating a role in differentiation. Variation in RA signaling thus follows a defined pattern and relates to invasive potential. A defective RA signaling might result in retinoid resistance and unpredictable clinical outcome observed in some neuroblastomas.
Joshi
Suchitra
S
Department of Internal Medicine, The Texas A&M University System Health Science Center, Central Texas Veterans Health Care System, Scott & White Clinic, 1901 South 1st Street, Temple, TX 76504, USA.
Guleria
Rakeshwar S
RS
Pan
Jing
J
Dipette
Donald
D
Singh
Ugra S
US
D000970:Antineoplastic Agents / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016259:Genes, myc; D006801:Humans; D020782:Matrix Metalloproteinases / Q000502:physiology*; D016501:Neurites / Q000187:drug effects; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D014212:Tretinoin / Q000494:pharmacology*; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D014212:Tretinoin; D020782:Matrix Metalloproteinases; D020764:cdc42 GTP-Binding Protein