Subamolide B Isolated from Medicinal Plant Cinnamomum subavenium Induces Cytotoxicity in Human Cutaneous Squamous Cell Carcinoma Cells through Mitochondrial and CHOP-Dependent Cell Death Pathways
Figure 7
A proposed model for the cytotoxic mechanisms of action of subamolide B. Subamolide B activates the cell death pathways mediated by FasL/Fas, mitochondria, and ER stress, as evidenced by FasL upregulation, BCL-2 downregulation/cytosolic release of cytochrome c, and induction of the UPR signaling pathway/CHOP upregulation, respectively. These cell death pathways lead to the activation of caspase-8, caspase-9, caspase-4, and caspase-3. Caspase activity and thus apoptosis are partially responsible for the cytotoxic activity of subamolide B, as cotreatment with the pan-caspase inhibitor z-VAD-fmk impairs but not abolishes subamolide B-induced cell death. FasL/Fas-mediated pathway appears dispensable for subamolide B’s cytotoxic activity, since blockade of this pathway by c- or the dominant-negative mutant of FADD (dnFADD) barely affects subamolide B-induced cell death. Conversely, BCL-2 overexpression or CHOP knockdown markedly enhances the survival of subamolide B-treated cells, confirming the requirement of mitochondrial and ER stress cell death pathways for subamolide B-induced cytotoxicity. Whether CHOP contributes to subamolide B’s cytotoxic action through suppression of BCL-2 and/or upregulation of BIM requires further validation.
