STAT3-mediated SMAD3 activation underlies Oncostatin M-induced Senescence

Abstract

Cytokines in the developing tumor microenvironment (TME) can drive transformation and subsequent progression toward metastasis. Elevated levels of the Interleukin-6 (IL-6) family cytokine Oncostatin M (OSM) in the breast TME correlate with aggressive, metastatic cancers, increased tumor recurrence, and poor patient prognosis. Paradoxically, OSM engages a tumor-suppressive, Signal Transducer and Activator of Transcription 3 (STAT3)-dependent senescence response in normal and non-transformed human mammary epithelial cells (HMEC). Here, we identify a novel link between OSM-activated STAT3 signaling and the Transforming Growth Factor-b (TGF-b) signaling pathway that engages senescence in HMEC. Inhibition of functional TGF-b/SMAD signaling by expressing a dominant-negative TGF-b receptor, treating with a TGF-b receptor inhibitor, or suppressing SMAD3 expression using a SMAD3-shRNA prevented OSMinduced senescence. OSM promoted a protein complex involving activated-STAT3 and SMAD3, induced the nuclear localization of SMAD3, and enhanced SMAD3-mediated transcription responsible for senescence. In contrast, expression of MYC (c-MYC) from a constitutive promoter abrogated senescence and strikingly, cooperated with OSM to promote a transformed phenotype, epithelial-mesenchymal transition (EMT), and invasiveness. Our findings suggest that a novel STAT3/SMAD3-signaling axis is required for OSM-mediated senescence that is coopted during the transformation process to confer aggressive cancer cell properties. Understanding how developing cancer cells bypass OSM/STAT3/SMAD3-mediated senescence may help identify novel targets for future "pro-senescence" therapies aiming to reengage this hidden tumor-suppressive response.

TGF-βRII Knock-down in Pancreatic Cancer Cells Promotes Tumor Growth and Gemcitabine Resistance. Importance of STAT3 Phosphorylation on S727

“…It was previously shown that STAT3-induced senescence requires functional TGFβR signaling and notably a functional SMAD3/SMAD4 pathway. STAT3 promotes SMAD3 nuclear localization [ 25 ]. We hypothesize that the TGF-βRIIKD-induced gemcitabine resistance, shown in the present manuscript, is mediated by STAT3 which similarly requires SMAD3/SMAD4 dependent pathway.…”

Role of JAK/STAT3 Signaling in the Regulation of Metastasis, the Transition of Cancer Stem Cells, and Chemoresistance of Cancer by Epithelial–Mesenchymal Transition

“…Members of the IL-6 cytokine family-including IL-6, CNTF, CT-1, CLCF1, LIF, and OSM-significantly increase STAT3 activation and the subpopulation of CSCs. Additionally, OSM-induced JAK2/STAT3 activation increases Snail and HAS2 levels, which act as CD44 ligands and induce nuclear accumulation of p-SMAD3 by STAT3/SMAD3 complex, and subsequently, facilitate EMT and generation of CSCs [35,172]. The STAT3-SMAD3 complex suppresses TGF-β1-mediated antiproliferative signaling by inhibiting the interaction between SMAD3 and SMAD4 [173].…”

Balancing STAT Activity as a Therapeutic Strategy

“…In non-transformed HMEC models, OSM engages senescence through a direct STAT3 interaction with mothers against decapentaplegic-3 (SMAD3). However, downstream constitutive expression of c-Myc could overcome OSM-induced senescence and drive EMT and invasion [137]. Beyond the genetic events that occur as a normal cell becomes transformed, cancer progression relies heavily on an evolving microenvironment, which impacts both the cancer cells and the immune system, ultimately influencing patient outcomes.…”