A novel interaction between procaspase 8 and SPARC enhances apoptosis and potentiates chemotherapy sensitivity in colorectal cancers.
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.
Tang
Michelle J
MJ
Division of Gastroenterology, University of British Columbia, 2775 Laurel Street, Vancouver, British Columbia, Canada.
Tai
Isabella T
IT
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism*; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D015676:Osteonectin / Q000378:metabolism / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D061945:Caspase Inhibitors; D015676:Osteonectin; D034741:RNA, Small Interfering; D053181:Caspase 8