Salidroside induces cell apoptosis and inhibits the invasiveness of HT29 colorectal cells by regulating protein kinase R, NF-κB and STAT3.

Abstract

BACKGROUND\nProtein kinase R (PKR) can suppress various types of solid tumors by inducing cellular oxidative stress and apoptosis. Likewise, Slaidorside, a plant flavonoid, was shown to have anti-tumorigenesis in many solid tumors.\n\n\nOBJECTIVE\nThis study evaluated anti-tumorigenesis of Salidorside in HT29 colorectal cancer and investigated if the underlying mechanism involves activation of PKR.\n\n\nMETHODS\nControl or PKR deficient cells were cultured in DMEM media treated with 100\xa0μM Salidorside and cell survival, apoptosis, and other biochemical-related markers were evaluated.\n\n\nRESULTS\nSalidorside significantly reduced cell survival and proliferation and increased the release of lactate dehydrogenase (LDH) and levels of single-stranded DNA (ssDNA). It also increased the protein levels of caspases 3 and 8. Concomitantly, Salidorside increased the protein level and activity of PKR and increased the expression of its downstream targets, p-eIF2α (Ser51), p53 MAPK, and p53. On the contrary, it inhibited the nuclear activation of STAT-3 and NF-κB p65. In PKR deficient cells, the partial effects of Salidorside on cell survival, proliferation, and apoptotic markers were observed coincided with no effects on the expression of eIF-2α, and JNK, p53, p38 MAPK, and caspase 8 but with a significant decrease in the nuclear activities of STAT3 and NF-κB.\n\n\nCONCLUSION\nSalidorside suppresses the tumorigenesis of HT29 CRC by increasing activation of eIF-2α and JNK and upregulation of p53, p38 MAPK, and caspase-8 through upregulating and activation of PKR. However, the tumor suppressor effect of Salidorside requires also inhibition of STAT3 and NF-κB in a PKR-independent mechanism.