Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade

Abstract

The receptor tyrosine kinase/PI3K/AKT/mammalian target of rapamycin (RTK/PI3K/AKT/mTOR) pathway is frequently altered in cancer, but the underlying mechanism leading to tumorigenesis by activated mTOR remains less clear. Here we show that mTOR is a positive regulator of Notch signaling in mouse and human cells, acting through induction of the STAT3/p63/Jagged signaling cascade. Furthermore, in response to differential cues from mTOR, we found that Notch served as a molecular switch to shift the balance between cell proliferation and differentiation. We determined that hyperactive mTOR signaling impaired cell differentiation of murine embryonic fibroblasts via potentiation of Notch signaling. Elevated mTOR signaling strongly correlated with enhanced Notch signaling in poorly differentiated but not in well-differentiated human breast cancers. Both human lung lymphangioleiomyomatosis (LAM) and mouse kidney tumors with hyperactive mTOR due to tumor suppressor TSC1 or TSC2 deficiency exhibited enhanced STAT3/p63/Notch signaling. Furthermore, tumorigenic potential of cells with uncontrolled mTOR signaling was suppressed by Notch inhibition. Our data therefore suggest that perturbation of cell differentiation by augmented Notch signaling might be responsible for the underdifferentiated phenotype displayed by certain tumors with an aberrantly activated RTK/PI3K/AKT/mTOR pathway. Additionally, the STAT3/p63/Notch axis may be a useful target for the treatment of cancers exhibiting hyperactive mTOR signaling.

Brain-expressed X-linked 2 Is Pivotal for Hyperactive Mechanistic Target of Rapamycin (mTOR)-mediated Tumorigenesis

“…Cell Culture, Reagents, and Plasmids-All mouse embryonic fibroblasts (MEFs) were described previously (25). Retroviral packaging PT67 cells were from Clontech.…”

“…Eight male mice were in each cohort. The subcutaneous tumor model was established as described previously (25,31).…”

“…Activation of STAT3 is detectable in many types of tumors (39). Because we have reported that mTOR up-regulates STAT3 (25,40), we investigated the regulation of BEX2 by STAT3. Overexpression of the constitutively activated STAT3 enhanced BEX2 expression (Fig.…”

p63 is a suppressor of tumorigenesis and metastasis interacting with mutant p53

“…107 (c) STAT3/p63 regulate Notch signaling downstream of TORC1 to affect the molecular switch of differentiation versus proliferation. 108 NF-kB counteracts this pathway p63 is a suppressor of tumorigenesis and metastasis G Melino cell cycle-related genes such as p21, 111,112 as well as apoptotic genes as mentioned above. TAp63g is the most active form at transcriptional level and accumulates in a phosphorylated form during DNA damage (by doxorubicin) with a drastically prolonged half-life.…”

“…mTOR and Notch signaling: mTOR is a positive regulator of Notch signaling via the induction of the STAT3/p63/Jagged signaling cascade. 108 Here, Notch seems to act a molecular switch between proliferation and differentiation, where high mTOR activity, via high Notch, impairs differentiation in human breast cancer lines.…”