RUNX2 and the PI3K/AKT axis reciprocal activation as a driving force for tumor progression

Abstract

From the first reported role of the transcription factor RUNX2 in osteoblast and chondrocyte differentiation and migration to its involvement in promigratory/proinvasive behavior of breast, prostate, and thyroid cancer cells, osteosarcoma, or melanoma cells, RUNX2 currently emerges as a key player in metastasis. In this review, we address the interaction of RUNX2 with the PI3K/AKT signaling pathway, one of the critical axes controlling cancer growth and metastasis. AKT, either by directly phosphorylating/activating RUNX2 or phosphorylating/inactivating regulators of RUNX2 stability or activity, contributes to RUNX2 transcriptional activity. Reciprocally, the activation of the PI3K/AKT pathway by RUNX2 regulation of its different components has been described in non-transformed and transformed cells. This mutual activation in the context of cancer cells exhibiting constitutive AKT activation and high levels of RUNX2 might constitute a major driving force in tumor progression and aggressiveness.

Fig. 1

Model of RUNX2 and PI3K/AKT reciprocal interaction as a driving force for tumor progression. a. AKT activity results in up regulation of RUNX2 mRNA, stabilization of RUNX2 protein or activation of RUNX2 transcriptional activity. b. RUNX2 transcriptional activity leads to higher expression of the PI3K subunits p110β and p85, AKT or mTOR and RICTOR, two major components of the mTORC2 complex. c. Mutual activation of AKT and RUNX2 in the context of cancer cells might favor tumor progression. A pioneering study [47] shows that RUNX2 and the PI3K/AKT axis are mutually dependent on each other in the regulation of osteoblast and chondrocyte differentiation and their migration. We propose that a similar feed-forward loop could operate in tumor cells to potentiate RUNX2 and PI3K/AKT activities and generate the pro-migratory and pro-invasive behavior of tumor cells. Studies described in paragraphs 1 and 2 support this hypothesis

Fig. 2

Summary of the interactions between the PI3K/AKT pathway and RUNX2 with integration of the TGFβ pathway. Some genes regulated by RUNX2 and supporting different aspects of tumor progression are represented. The activation of growth factor receptors, such as G-protein coupled receptors (GPCR), receptor tyrosine kinases (RTKs), TGFβ receptor, results in successive activation of PI3K and AKT. PTEN inactivation also results in activation of PI3K and AKT. AKT activation positively regulates RUNX2 expression and activity by direct and indirect mechanisms as shown in Fig. 1A. Reciprocally, RUNX2 activates the PI3K/AKT pathway by regulation if its components, PI3K and AKT, or regulation of mTOR and RICTOR, two majors components of mTORC2, which phosphorylates AKT on serine 473. Upon receptor activation, the kinases ERK and p38 also phosphorylate and activate RUNX2. Through partnering with SMADs transcription factors, RUNX2, (TGFβ target gene itself) activates the expression of genes involved in EMT, invasion and the metastatic cascade, angiogenesis and bone disease. OPN: osteopontin; BSP: Bone sialoprotein; MMP: Matrix metalloproteinase; FAK: Focal adhesion kinase; IHH: Indian hedgehog; PTHrP: Parathyroid hormone-related protein; VEGF: Vascular endothelial growth factor; IL8: Interleukin-8. IL11: Interleukin-11; PAI-1: Plasminogen activator inhibitor-1