Membrane-linked sialidase Neu3 is a key enzyme for the extralysosomal catabolism of gangliosides. In this respect, it regulates pivotal cell surface events, including trans-membrane signaling, and plays an essential role in carcinogenesis. In this report, we demonstrated that acute lymphoblastic leukemia (ALL), lymphoblasts (primary cells from patients and cell lines) are characterized by a marked down-regulation of Neu3 in terms of both gene expression (-30 to 40%) and enzymatic activity toward ganglioside GD1a (-25.6 to 30.6%), when compared with cells from healthy controls. Induced overexpression of Neu3 in the ALL-cell line, MOLT-4, led to a significant increase of ceramide (+66%) and to a parallel decrease of lactosylceramide (-55%). These events strongly guided lymphoblasts to apoptosis, as we assessed by the decrease in Bcl2/Bax ratio, the accumulation of Neu3 transfected cells in the sub G0-G1 phase of the cell cycle, the enhanced annexin-V positivity, the higher cleavage of procaspase-3. Therefore, the reduced expression of Neu3 in ALL could help lymphoblasts to survive, maintaining the cellular content of ceramide below a critical level. Interestingly, we found that Neu3 activity varied in relation to disease progression, increasing in clinical remission after chemotherapy, and decreasing again in patients that relapsed. In addition, a negative correlation was observed between Neu3 expression and the percentage of the ALL marker 9-OAcGD3 positive cells. Consequently, Neu3 could represent a new potent biomarker in childhood ALL, to assess the efficacy of therapeutic protocols and to rapidly identify an eventual relapse.
Down regulation of membrane-bound Neu3 constitutes a new potential marker for childhood acute lymphoblastic leukemia and induces apoptosis suppression of neoplastic cells / C. Mandal, C.A. Tringali, S. Mondal, L. Anastasia, S. Chandra, B. Venerando, C. Mandal. - In: INTERNATIONAL JOURNAL OF CANCER. - ISSN 0020-7136. - 126:2(2010 Jan), pp. 337-349.
|Titolo:||Down regulation of membrane-bound Neu3 constitutes a new potential marker for childhood acute lymphoblastic leukemia and induces apoptosis suppression of neoplastic cells|
TRINGALI, CRISTINA ALESSANDRA (Secondo)
VENERANDO, BRUNO (Penultimo)
|Parole Chiave:||acute lymphoblastic leukemia (ALL) ; sialidase Neu3 ; apoptosis ; 9-O-acetylated GD3 ; gangliosides|
|Settore Scientifico Disciplinare:||Settore BIO/10 - Biochimica|
Settore BIO/12 - Biochimica Clinica e Biologia Molecolare Clinica
|Data di pubblicazione:||gen-2010|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1002/ijc.24733|
|Appare nelle tipologie:||01 - Articolo su periodico|