Regulation of the Notch-ATM-abl axis by geranylgeranyl diphosphate synthase inhibition

Abstract

Notch proteins drive oncogenesis of many cancers, most prominently T-cell acute lymphoblastic leukemia (T-ALL). Because geranylgeranylated Rab proteins regulate Notch processing, we hypothesized that inhibition of geranylgeranyl diphosphate synthase (GGDPS) would impair Notch processing and reduce viability of T-ALL cells that express Notch. Here, we show that GGDPS inhibition reduces Notch1 expression and impairs the proliferation of T-ALL cells. GGDPS inhibition also reduces Rab7 membrane association and depletes Notch1 mRNA. GGDPS inhibition increases phosphorylation of histone H2A.X, and inhibitors of ataxia telangiectasia-mutated kinase (ATM) mitigate GGDPS inhibitor-induced apoptosis. GGDPS inhibition also influences c-abl activity downstream of caspases, and inhibitors of these enzymes prevent GGDPS inhibitor-induced apoptosis. Surprisingly, induction of apoptosis by GGDPS inhibition is reduced by co-treatment with γ-secretase inhibitors. While inhibitors of γ-secretase deplete one specific form of the Notch1 intracellular domain (NICD), they also increase Notch1 mRNA expression and increase alternate forms of Notch1 protein expression in cells treated with a GGDPS inhibitor. Furthermore, inhibitors of γ-secretase and ATM increase Notch1 mRNA stability independent of GGDPS inhibition. These results provide a model by which T-ALL cells use Notch1 to avoid DNA-damage-induced apoptosis, and can be overcome by inhibition of GGDPS through effects on Notch1 expression and its subsequent response.

MicroRNA-874 targets phosphomevalonate kinase and inhibits cancer cell growth via the mevalonate pathway

“…Agabiti et al . reported that geranylgeranyl diphosphate synthase, which is an enzyme in the isoprenoid biosynthesis pathway that produces a pathway that produces GGPP, reduces the expression of Notch1 and affects the expression of its downstream target, c-Myc 47 .…”

Geranylgeranyl diphosphate synthase: Role in human health, disease and potential therapeutic target

“…DGBP was also found to induce apoptosis in T‐cell acute lymphoblastic leukaemia (T‐ALL) cell lines. 200 A potential mechanism was postulated, connecting disruption of Rab7 localisation due to GGPP depletion with inhibition of Notch1 expression. 201 Notch1 is altered in over 60% of T‐ALL cases and has been shown to promote proliferation and differentiation.…”

“…Addition of GGPP following DGBP treatment was shown to abrogate the anti‐proliferative effects, indicating GGPP depletion to be the key mechanism underlying DGBP effects. DGBP was also found to induce apoptosis in T‐cell acute lymphoblastic leukaemia (T‐ALL) cell lines 200 . A potential mechanism was postulated, connecting disruption of Rab7 localisation due to GGPP depletion with inhibition of Notch1 expression 201 .…”

Advances of target therapy on NOTCH1 signaling pathway in T-cell acute lymphoblastic leukemia

“…In addition to the above studies, there are other experimental protocols targeting NOTCH1 [51,52], such as the proteasome inhibitor (bortezomib) [53], histone deacetylase inhibitor (panobinostat) [54], HSP90 inhibitor [55,56], insecticide (mebendazole) [57], geranylgeranyl diphosphate synthase inhibition (digeranyl bisphosphonate, DGBP) [58], and the antibody Rova-T against its ligand DLL3 [ 59 ] . Other natural anti-NOTCH compounds have been shown to inhibit NOTCH1 mutant T-ALL cells, such as plant polyphenol flavonoids [60], artemisinin [61], etc.…”