Fig. 5.

TNFR2-mediated apoptosis resistance in BC cells. TNFR2 triggers the activation of various proteins to help BC escape apoptosis. TNFR2-mediated Akt, NF-κB, and c-FLIP activation stimulate c-FLIP to activate FADD, RIPK1, TRAF2, and TRADD, inhibiting pro-Cas 8 and pro-Cas 10. While Akt activation leads to apoptosis via IKK/DR activation, inducing TNF-α and TWEAK, NF-κB activation induces a series of anti-apoptotic proteins, including Bcl-2, Bcl-XL, Bcl-W, xIAP, cIAP1/2, A1/BFL-1, Cyclin D1, STAT3, and MCL-1 to inhibit apoptosis. TNFR2 may also activate MEK/ERK and PI3K/Akt. MEK/ERK deactivates the protein Bim, while PI3K/Akt deactivates GSK-3, BAD, and FKHR. Together, these proteins inhibit apoptosis, leading to BC cell survival and growth. TNFR2, tumor necrosis receptor type 2; TNF-α, tumor necrosis factor; TRAF, TNF receptor associated factor; c-FLIP, cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein; FADD, fas-associated protein-death domain; RIPK1, receptor-interacting protein kinase 1; TRADD, TNFR1-associated death domain; TWEAK, tumor necrosis-like weak inducer of apoptosis; BAD, Bcl-2-associated agonist of cell death; pro-cas8, pro-caspase 8; pro-cas10, pro-caspase 10; Bcl-2, B cell lymphoma 2; Bcl-XL, B cell lymphoma extra-large, Bcl-W, B cell lymphoma W; xIAP, X-linked inhibitor of apoptosis protein; cIAP, cellular inhibitor of apoptosis; STAT3, signal transducer and activator of transcription 3; MCL-1, Myeloid cell leukemia 1; GSK-3, glycogen kinase synthase-3; FKHR, fork-head in rhabdomyosarcoma; PI3K, phosphoinositide 3-kinases; Akt, protein kinase B/serine-threonine kinase; ERK, extracellular signal-regulated kinase