Apoptosis Induced by TGF-β1 in Burkitt’s Lymphoma Cells Is Caspase 8 Dependent But Is Death Receptor Independent

Abstract

TGF-β is a potent inducer of apoptosis in many Burkitt’s lymphoma (BL) cell lines. In this study, we characterize this apoptotic process in the EBV-negative BL41 cell line. Induction of apoptosis was detected as early as 8 h after TGF-β treatment, as assayed by TUNEL and poly(ADP-ribose) polymerase cleavage. FACS analysis demonstrates that this proceeds predominately from the G1, but also from the G2/M phases of the cell cycle. We observed no early detectable changes in the steady-state levels of Bcl-2 and several of its family members after TGF-β treatment. We detected cleavage of caspases 2, 3, 7, 8, and 9 into their active subunits. Consistent with the involvement of these enzymes in TGF-β-mediated apoptosis, the broad spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp(Ome)-flouromethylketone (ZVAD-fmk) blocked TGF-β-induced apoptosis and revealed a G1 arrest in treated cells. Use of specific caspase inhibitors revealed that the induction of apoptosis is caspase 8 dependent, but caspase 3 independent. Activation of caspase 8 has been shown to be a critical event in death receptor-mediated apoptosis. However, TGF-β treatment of BL41 cells was found not to affect the cell surface expression of Fas, TNF-R1, DR3, DR4, or DR5, or the steady-state expression levels of Fas ligand, TNF-R1, DR3, DR4, and DR5. Furthermore, blocking experiments indicated that TGF-β-mediated apoptosis is not dependent on Fas ligand, TNF-α, tumor necrosis-like apoptosis-inducing ligand, or TNF-like weak inducer of apoptosis signaling. Therefore, it appears that TGF-β induces apoptosis in BL cell lines via caspase 8 in a death receptor-independent fashion.

Downregulation of IL-6-induced STAT3 tyrosine phosphorylation by TGF-β1 is mediated by caspase-dependent and -independent processes

“…38 Recently, it has been shown in Burkitt lymphoma cells that TGF-␤1 could induce apoptosis in a caspase8-dependent manner which could be blocked by the caspase inhibitor Z-VAD-fmk. 36 In the AML cases under investigation in this study, it was shown that the TGF-␤1-and VP16-induced apoptotic process was caspase-dependent resulting in the selective degradation of JAK and PKB proteins without affecting the ERK pathway. The degradation of the JAK proteins was shown to be able to disrupt the IL-6 signaling, resulting in an attenuated STAT3 tyrosine phosphorylation.…”

“…Because apoptosis induction by TGF-␤1 has been described, 30,31,35,36 we investigated whether this might be the case in the responding patients. Blast cells of AML No.…”

The signaling pathways of Epstein-Barr virus-encoded latent membrane protein 2A (LMP2A) in latency and cancer

“…The inhibition of the TGF-β pathway is one example. TGF-β1 induces apoptosis by activating caspase [134][135][136][137]. LMP2A inhibits TGF-β1-induced caspase activity and apoptosis through the activation of the PI3-K/Akt pathway via phosphorylation of Akt at its serine residue [132,138].…”

Tubular Cell HIV-1 gp120 Expression Induces Caspase 8 Activation and Apoptosis

“…[44][45][46] However, activation of caspase-8 activation has been reported to be independent of FasL pathway activation. [47] HIV-1 has been reported to enhance tubular cell apoptosis. [33,37,48] Bruggeman et al evaluated the importance of HIV-1 transgene in the development of HIVAN.…”