Metformin has been shown to inhibit
tumor growth in xenograft rodent models of adult
cancers, and various human clinical trials are in progress. However, the precise molecular mechanisms of
metformin action are largely unknown. In the present study we examined the anti-
tumor activity of
metformin against
neuroblastoma, and determined the underlying signaling mechanisms. Using human
neuroblastoma xenograft mice, we demonstrated that
oral administration of
metformin (100 and 250 mg/kg
body weight) significantly inhibited the growth of
tumors. The interference of
metformin in spheroid formation further confirmed the anti-
tumor activity of
metformin. In
tumors, the activation of Rac1 (GTP-Rac1) and Cdc42 (GTP-Cdc42) was increased while RhoA activation (
GTP-RhoA) was decreased by
metformin. It also induced phosphorylation of JNK and inhibited the phosphorylation of ERK1/2 without affecting
p38 MAP Kinase.
Infection of cells by adenoviruses expressing dominant negative Rac1 (Rac1-N17), Cdc42 (Cdc42-N17) or constitutively active RhoA (RhoA-V14), or incubation of cells with pharmacological inhibitors of Rac1 (
NSC23766) or Cdc42 (ML141) significantly protected
neuroblastoma cells from
metformin-induced apoptosis. Additionally, inhibition of JNK activity along with Rac1 or Cdc42 attenuated cytotoxic effects of
metformin. These studies demonstrated that
metformin impairs
Rho GTPases signaling to induce apoptosis via JNK pathway.