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Updated: Jul 11, 2026
Measuring Composition of CD95 Death-Inducing Signaling Complex and Processing of Procaspase-8 in this Complex
Published on: August 2, 2021
A novel interaction between procaspase 8 and SPARC enhances apoptosis and potentiates chemotherapy sensitivity in
Michelle J Tang1, Isabella T Tai
1Division of Gastroenterology, University of British Columbia, 2775 Laurel Street, Vancouver, British Columbia, Canada.
Abstract:
Chemotherapy resistance accounts for the high mortality rates in patients with advanced cancers. We previously used a genomics approach to determine novel genes associated with this phenomenon and identified secreted protein acidic and rich in cysteine (SPARC) as a chemosensitizer capable of reversing therapy resistance in colorectal cancer cells by enhancing apoptosis in vitro and tumor regression in vivo. Here, we examined the mechanisms by which SPARC enhances apoptosis in the presence of chemotherapy. We show that SPARC potentiates apoptosis by augmenting the signaling cascade in a caspase-8-dependent manner, because apoptosis can be abolished by caspase 8 small interfering RNA in the presence of SPARC. This occurs independently of death receptor activation and leads to downstream involvement of Bid and subsequent apoptosis. Interestingly, this results from an interaction between SPARC and the N terminus of the procaspase-8 DED-containing domain. These exciting findings provide an initial map of the apoptosis signaling events mediated by SPARC and how this can ultimately result in the reversal of chemotherapy resistance and enhanced tumor regression. This signaling cascade can be exploited therapeutically and may have potential clinical implications for patients with advanced and therapy-refractory cancers.
Insights
Secreted protein acidic and rich in cysteine (SPARC) reverses chemotherapy resistance by enhancing apoptosis through a caspase-8-dependent pathway. This discovery offers potential therapeutic strategies for advanced, refractory cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Chemotherapy resistance is a major cause of mortality in advanced cancers.
- Secreted protein acidic and rich in cysteine (SPARC) was previously identified as a potential chemosensitizer.
- SPARC demonstrated the ability to reverse therapy resistance in colorectal cancer cells.
Purpose of the Study:
- To elucidate the mechanisms by which SPARC enhances apoptosis in the presence of chemotherapy.
- To investigate the role of SPARC in overcoming chemotherapy resistance.
Main Methods:
- Investigated SPARC-mediated apoptosis signaling pathways.
- Utilized caspase-8 small interfering RNA to assess the dependency of apoptosis on caspase-8.
- Examined the interaction between SPARC and procaspase-8.
Main Results:
- SPARC potentiates apoptosis via a caspase-8-dependent signaling cascade.
- Apoptosis induction by SPARC is independent of death receptor activation.
- SPARC interacts with the N-terminal DED domain of procaspase-8, leading to downstream Bid activation and apoptosis.
- SPARC enhances tumor regression in vivo.
Conclusions:
- SPARC reverses chemotherapy resistance by modulating the caspase-8 apoptotic pathway.
- The SPARC-mediated signaling cascade offers a potential therapeutic target for advanced and therapy-refractory cancers.
- Findings provide a mechanistic understanding of SPARC's role in chemosensitization and tumor regression.
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