Silencer of death domains controls cell death through tumour necrosis factor-receptor 1 and caspase-10 in acute...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Cell Death Mechanisms

Background:

• Apoptosis resistance is a major challenge in cancer treatment, leading to drug resistance and therapeutic failure.
• Wnt signaling plays a role in acute lymphoblastic leukemia (ALL) cell proliferation and survival, but its inhibition does not induce ALL cell death.
• NO-aspirin demonstrates efficacy against solid tumors and inhibits Wnt signaling.

Purpose of the Study:

• To investigate the mechanism by which NO-aspirin induces cell death in acute lymphoblastic leukemia (ALL).
• To explore the role of the extrinsic death pathway, caspase-10, and silencer of death domain (SODD) in NO-aspirin-mediated apoptosis in ALL.

Main Methods:

• Treatment of B lineage ALL cell lines and patient-derived ALL cells with NO-aspirin.
• Analysis of apoptosis induction via the extrinsic death pathway, focusing on caspase-10 and the death-inducing signaling complex (DISC).
• Assessment of TNF-R1 and TNF-α levels, silencer of death domain (SODD) expression, and SODD knockdown using lentiviral shRNA.

Main Results:

• NO-aspirin treatment induced rapid apoptotic cell death in ALL cells through the extrinsic death pathway.
• Apoptosis was dependent on caspase-10 and the formation of a ligand-independent DISC involving TNF-R1.
• NO-aspirin reduced SODD expression, and SODD knockdown suppressed ALL cell expansion, highlighting SODD's importance for ALL cell survival.

Conclusions:

• NO-aspirin triggers apoptosis in ALL cells via a caspase-10-dependent extrinsic pathway, independent of TNF-α.
• Silencer of death domain (SODD) is crucial for ALL cell survival and its reduction by NO-aspirin contributes to cell death.
• Targeting over-expressed SODD and caspase-10 presents a potential therapeutic strategy for ALL and other cancers.