| Resveratrol, found in grape skin, inhibits tumorigenesis and aging. However, much is unknown about the target of resveratrol. Previously, our laboratory observed perinuclear mitochondrial clustering prior to apoptosis in cancer cells exposed to analogs of resveratrol, MR-4 (3,4,5,4'-tetramethoxy- trans-stilbene) and MC-4 (3,4,5,4'-tetramethoxy-cis -stilbene) (Gosslau et al., 2008), suggesting a role for mitochondria in the action of these stilbene polyphenols. Therefore, I used mitochondrial fission and fusion knockout cells to determine the pro-apoptotic target of these stilbene polyphenol analogs, which exhibited a 2-fold decrease in IC50 value in fusion knockout cells. Thus, mitochondrial shape partially affected apoptotic signaling.;It is known that these stilbene polyphenols induce apoptosis in cancer cells (Gosslau et al., 2005; Gosslau et al., 2008), but their mechanism of action is unclear. Knockout cell lines with pro-apoptotic genes deleted (p53, Bax, PUMA, RAIDD, Bid, Caspase-2, Bax/Bak, Apaf-1) were used to distinguish if the intrinsic apoptotic pathway was involved in stilbene polyphenol action. However, knockout cells did not exhibit significant changes in response to stilbene polyphenols, compared to their parental cell line, suggesting these individual components of apoptotic signaling may not play a major role in their action.;SIRT1, a putative target of resveratrol, was analyzed for its role in the pro-apoptotic action of stilbene polyphenol analogs by reporter gene, HSF1 activation, and cell viability assays. Although SIRT1 was a target of stilbene polyphenols, it was not involved in their pro-apoptotic action; IC 50 values for stilbene polyphenols in SIRT1 knockout cells remained the same as in wildtype cells.;SIRT1 is involved in the heat shock response; therefore, we explored the role of heat treatment in cancer cell killing. HeLa (cervical cancer) cells exposed to heat (51°C, 30 min) remained viable after recovery, as opposed to Caco-2 and other colon cancer cells, melanoma, glioma, osteosarcoma, glioblastoma, prostrate, and breast cancer cells. Importantly, we observed a relationship between eIF5A loss and hyperthermia-induced cell death.;My data indicate SIRT1 is a target of stilbene polyphenols, but is not involved in their apoptotic action. Further, hyperthermia killing is cell-specific and correlates with eIF5A depletion. Therefore, stilbene polyphenols and hyperthermia are viable options in cancer therapy. |
