Junhua Liao; Tang Zhu; Jie Wu; Mingyu Huang; Xianxian Luo
Abstract
Transforming growth factor-β (TGF-β) signaling plays a complex and dual role in regulating cellular senescence and tumor progression. In normal tissues, TGF-β acts as a tumor suppressor by regulating the cell cycle, inducing apoptosis, and maintaining the integrity of the extracellular ...
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Transforming growth factor-β (TGF-β) signaling plays a complex and dual role in regulating cellular senescence and tumor progression. In normal tissues, TGF-β acts as a tumor suppressor by regulating the cell cycle, inducing apoptosis, and maintaining the integrity of the extracellular matrix (ECM). These functions collectively restrict tumor initiation and support tissue homeostasis. However, in the tumor microenvironment, sustained TGF-β signaling frequently switches to a tumor-promoting role, driving tumor cell proliferation, metastatic dissemination, immune evasion, and therapy resistance. This review aims to clarify the dual role of TGF-β signaling in cellular senescence and tumor progression. It focuses on the molecular mechanisms that drive its transition between tumor suppression and tumor promotion in various biological contexts. We analyze the key determinants governing this functional switch, including tumor type, cellular environment, and signaling crosstalk. Furthermore, we critically evaluate the clinical challenges of therapeutic TGF-β targeting. We highlight emerging strategies to therapeutically modulate TGF-β signaling, focusing on precision medicine approaches that reconcile its tumor-suppressive and oncogenic functions. By providing a comprehensive understanding of TGF-β's dual role, this review offers new insights that may guide personalized cancer therapies and optimize treatment strategies for improved clinical outcomes.
Saeid Taghiloo; Abolghasem Ajami; Reza Alizadeh-Navaei; Ehsan Zaboli; Hossein Asgarian-Omran
Abstract
Background: Several PI3K/Akt/mTOR pathway inhibitors and TLR agonists induce tumor cell death. However, the mechanisms of these therapeutic approaches in acute myeloid leukemia (AML) cells are still unknown. Objectives: To investigate the effects of BEZ235, as a dual inhibitor of PI3K and mTOR pathways, ...
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Background: Several PI3K/Akt/mTOR pathway inhibitors and TLR agonists induce tumor cell death. However, the mechanisms of these therapeutic approaches in acute myeloid leukemia (AML) cells are still unknown. Objectives: To investigate the effects of BEZ235, as a dual inhibitor of PI3K and mTOR pathways, and TLR7/8 agonist R848 on the expression and regulation of the immune inhibitory molecules in myeloid leukemia cells. Methods: WEHI-3 leukemia cells were incubated with dual PI3K and mTOR inhibitor BEZ235 and TLR7/8 agonist R848 for 48 hrs. Firstly, cell viability was assessed by MTT method. The semi-quantitative relative mRNA expression of Galectin-9 (Gal-9), PD-L1, PVR, and STAT3 was assessed according to HPRT as a housekeeping gene. Finally, the protein expression of phosphorylated STAT3 was evaluated by western blotting analysis. Results: WEHI-3 cells showed growth inhibition following treatment with BEZ235 and R848 whose combination exerted more proliferation arrest. The mRNA expression of Gal-9, PD-L1 and PVR immune checkpoint molecules significantly reduced in treated cells with BEZ235 and R848. Combined treatment indicated more reduction compared with the single treatment. Finally, the expression and phosphorylation of STAT3 were down-regulated after a single or dual treatment with BEZ235 and R848. Conclusion: Our results conclude that treatment with the combination of BEZ235 and R848 interferes with immune evasion mechanisms through STAT3-signaling pathway in WEHI-3 leukemia cells.
