Tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL) is an attractive target for
cancer therapy due to its ability to selectively induce apoptosis in
cancer cells, without causing significant toxicity in normal tissues. We previously reported that
galactoxyloglucan (
PST001) possesses significant antitumor and immunomodulatory properties. However, the exact mechanism in mediating this anticancer effect is unknown. This study, for the first time, indicated that
PST001 sensitizes
non-small cell lung cancer (A549) and nasopharyngeal (KB) cells to TRAIL-mediated apoptosis. In vitro studies suggested that
PST001 induced apoptosis primarily via
death receptors and predominantly activated
caspases belonging to the extrinsic apoptotic cascade. Microarray profiling of
PST001 treated A549 and KB cells showed the suppression of
survivin (BIRC5) and anti-apoptotic Bcl-2, as well as increased
cytochrome C. TaqMan low density array analysis of A549 cells also confirmed that the induction of apoptosis by the
polysaccharide occurred through the TRAIL-DR4/DR5 pathways. This was finally confirmed by in silico analysis, which revealed that
PST001 binds to TRAIL-DR4/DR5 complexes more strongly than TNF and
Fas ligand-receptor complexes. In summary, our results suggest the potential of
PST001 to be developed as an
anticancer agent that not only preserves innate
biological activity of TRAIL, but also sensitizes
cancer cells to TRAIL-mediated apoptosis.