Altered intracellular calcium fluxes in pancreatic cancer induced diabetes mellitus: Relevance of the S100A8 N-terminal peptide (NT-S100A8).
After isolating NT-S100A8 from pancreatic cancer (PC) tissue of diabetic patients, we verified whether this peptide alters PC cell growth and invasion and/or insulin release and [Ca(2+)](i) oscillations of insulin secreting cells and/or insulin signaling. BxPC3, Capan1, MiaPaCa2, Panc1 (PC cell lines) cell growth, and invasion were assessed in the absence or presence of 50, 200, and 500 nM NT-S100A8. In NT-S100A8 stimulated β-TC6 (insulinoma cell line) culture medium, insulin and [Ca(2+)] were measured at 2, 3, 5, 10, 15, 30, and 60 min, and [Ca(2+)](i) oscillations were monitored (epifluorescence) for 3 min. Five hundred nanomolars NT-S100A8 stimulated BxPC3 cell growth only and dose dependently reduced MiaPaCa2 and Panc1 invasion. Five hundred nanomolars NT-S100A8 induced a rapid insulin release and enhanced β-TC6 [Ca(2+)](i) oscillations after both one (F = 6.05, P < 0.01) and 2 min (F = 7.42, P < 0.01). In the presence of NT-S100A8, [Ca(2+)] in β-TC6 culture medium significantly decreased with respect to control cells (F = 6.3, P < 0.01). NT-S100A8 did not counteract insulin induced phosphorylation of the insulin receptor, Akt and IκB-α, but it independently activated Akt and NF-κB signaling in PC cells. In conclusion, NT-S100A8 exerts a mild effect on PC cell growth, while it reduces PC cell invasion, possibly by Akt and NF-κB signaling, NT-S100A8 enhances [Ca(2+)](i) oscillations and insulin release, probably by inducing Ca(2+) influx from the extracellular space, but it does not interfere with insulin signaling.
Basso
Daniela
D
Department of Laboratory Medicine, University of Padua, Padua, Italy.
Greco
Eliana
E
Padoan
Andrea
A
Fogar
Paola
P
Scorzeto
Michele
M
Fadi
Elisa
E
Bozzato
Dania
D
Moz
Stefania
S
Navaglia
Filippo
F
Zambon
Carlo-Federico
CF
Seraglia
Roberta
R
De Carlo
Eugenio
E
Valerio
Anna
A
Reggiani
Carlo
C
Pedrazzoli
Sergio
S
Plebani
Mario
M
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D040501:Calgranulin A / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003920:Diabetes Mellitus / Q000209:etiology* / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000150:complications* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D010455:Peptides / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000502:physiology
D040501:Calgranulin A; D007328:Insulin; D010455:Peptides; D002118:Calcium