TY - JOUR
T1 - A novel insight into the anticancer mechanism of metformin in pancreatic neuroendocrine tumor cells
AU - Vitali, E.
AU - Boemi, I.
AU - Piccini, S.
AU - Tarantola, G.
AU - Smiroldo, V.
AU - Lavezzi, E.
AU - Brambilla, T.
AU - Zerbi, A.
AU - Carnaghi, C.
AU - Mantovani, G.
AU - Spada, A.
AU - Lania, A. G.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - The antidiabetic drug metformin displays anticancer properties in several neoplasms. In pituitary NETs, aryl hydrocarbon receptor-interacting protein (AIP) is up-regulated by the somatostatin analog octreotide. Metformin inhibited QGP-1 cell proliferation in a dose- and time-dependent manner, at concentrations similar to those achievable in treated patients (−31 ± 12%, p < 0.05 vs basal at 100 μM). Moreover, metformin decreased pancreatic neuroendocrine tumors (PAN-NETs) cell proliferation (−62 ± 15%, p < 0.0001 vs basal at 10 mM), without any additive effect when combined with octreotide. Both octreotide and metformin induced AIP up-regulation. AIP silencing abolished the reduction of mTOR phosphorylation induced by metformin and octreotide. Moreover, metformin decreased HSP70, increased Zac1 and AhR expression; these effects were abolished in AIP silenced QGP-1 cells. In conclusion, metformin acts as an anticancer agent in PAN-NET cells, its activity is mediated by AIP and its interacting proteins. These findings provide a novel insight into the antitumorigenic mechanism of metformin.
AB - The antidiabetic drug metformin displays anticancer properties in several neoplasms. In pituitary NETs, aryl hydrocarbon receptor-interacting protein (AIP) is up-regulated by the somatostatin analog octreotide. Metformin inhibited QGP-1 cell proliferation in a dose- and time-dependent manner, at concentrations similar to those achievable in treated patients (−31 ± 12%, p < 0.05 vs basal at 100 μM). Moreover, metformin decreased pancreatic neuroendocrine tumors (PAN-NETs) cell proliferation (−62 ± 15%, p < 0.0001 vs basal at 10 mM), without any additive effect when combined with octreotide. Both octreotide and metformin induced AIP up-regulation. AIP silencing abolished the reduction of mTOR phosphorylation induced by metformin and octreotide. Moreover, metformin decreased HSP70, increased Zac1 and AhR expression; these effects were abolished in AIP silenced QGP-1 cells. In conclusion, metformin acts as an anticancer agent in PAN-NET cells, its activity is mediated by AIP and its interacting proteins. These findings provide a novel insight into the antitumorigenic mechanism of metformin.
KW - AIP
KW - Metformin
KW - mTOR
KW - Octreotide
KW - Pancreatic neuroendocrine tumors
UR - http://www.scopus.com/inward/record.url?scp=85082677184&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85082677184&partnerID=8YFLogxK
U2 - 10.1016/j.mce.2020.110803
DO - 10.1016/j.mce.2020.110803
M3 - Article
C2 - 32251713
AN - SCOPUS:85082677184
VL - 509
JO - Molecular and Cellular Endocrinology
JF - Molecular and Cellular Endocrinology
SN - 0303-7207
M1 - 110803
ER -