Constitutively active Akt1 expression in mouse pancreas requires S6 kinase 1 for insulinoma formation

Abstract

Factors that promote pancreatic β cell growth and function are potential therapeutic targets for diabetes mellitus. In mice, genetic experiments suggest that signaling cascades initiated by insulin and IGFs positively regulate β cell mass and insulin secretion. Akt and S6 kinase (S6K) family members are activated as part of these signaling cascades, but how the interplay between these proteins controls β cell growth and function has not been determined. Here, we found that although transgenic mice overexpressing the constitutively active form of Akt1 under the rat insulin promoter (RIP-MyrAkt1 mice) had enlarged β cells and high plasma insulin levels, leading to improved glucose tolerance, a substantial proportion of the mice developed insulinomas later in life, which caused decreased viability. This oncogenic transformation tightly correlated with nuclear exclusion of the tumor suppressor PTEN. To address the role of the mammalian target of rapamycin (mTOR) substrate S6K1 in the MyrAkt1-mediated phenotype, we crossed RIP-MyrAkt1 and S6K1-deficient mice. The resulting mice displayed reduced insulinemia and glycemia compared with RIP-MyrAkt1 mice due to a combined effect of improved insulin secretion and insulin sensitivity. Importantly, although the increase in β cell size in RIP-MyrAkt1 mice was not affected by S6K1 deficiency, the hyperplastic transformation required S6K1. Our results therefore identify S6K1 as a critical element for MyrAkt1-induced tumor formation and suggest that it may represent a useful target for anticancer therapy downstream of mTOR.

mTORC1 signaling and regulation of pancreatic β-cell mass

“…76 Uncertainties still remain as to (1) what are the underlying mechanisms and key downstream effector(s) by activation of AKT signaling, implicating this kinase in regulation of β-cell cell cycle progression. 91 Little is known about the signaling events downstream of S6K. The importance of ribosomal S6 protein was assessed using knock-in mice containing alanine substitutions at all five phosphorylatable serine residues of their S6 protein.…”

Phosphorylation of Ribosomal Protein S6 Attenuates DNA Damage and Tumor Suppression during Development of Pancreatic Cancer

“…Several studies have shown that pharmacologic inhibition of mTORC1 can attenuate the growth of pancreatic cancer cell lines in vitro and in vivo (20)(21)(22), but the identity of downstream effectors remains largely unknown. S6K has been implicated in tumorigenicity (23) but not in the context of PDAC. S6K has multiple substrates, including rpS6, whose phosphorylation is tightly coupled to mTORC1 activity (24).…”

Identification of a Dual Inhibitor of Janus Kinase 2 (JAK2) and p70 Ribosomal S6 Kinase1 (S6K1) Pathways

“…Because of its pivotal role in these processes, S6K has been recognized as a promising therapeutic target for a number of human cancers (10,12,14,15). Genetic and pharmacological suppression of the S6K pathway has been shown to prevent malignant transformation and block cancer progression (9,(15)(16)(17). However, recent reports have exposed some limitations to the singular targeting of the S6K pathway alone, as such approaches can primarily induce cell cycle arrest with minimal induction of cell death (10,18).…”