Tanshinone IIA increases protein expression levels of PERK, ATF6, IRE1 alpha, CHOP, caspase-3 and caspase-12 in pancreatic cancer BxPC-3 cell-derived xenograft tumors

摘要

Tanshinone (Tan)-IIA is a derivative of phenanthrenequinone and the main active ingredient isolated from Salviae miltiorrhizae radix (Danshen). Previous studies have demonstrated that Tan-IIA increased the protein expressions levels of protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor (ATF) 6, caspase-12 and CCAAT-enhancer-binding protein homologous protein (CHOP), to induce endoplasmic reticulum (ER) stress and apoptosis in human pancreatic cancer BxPC-3 cells. However, to the best of our knowledge, the effects of Tan-IIA on pancreatic cancer cells have not been investigated in vivo. Further studies are required to elucidate the therapeutic potential of Tan-IIA in inducing ER stress in cancer cells in vivo. The present study aimed to investigate the effects of Tan-IIA on the expression of ER stress-related proteins in BxPC-3-derived xenograft tumors. A total of 30 male severe combined immunodeficiency mice (age, 4 weeks) were implanted with BxPC-3 cells (2x10(6)/0.2 ml) and subsequently treated with various doses of Tan-IIA (0, 30 and 90 mg/kg) for 4 weeks. After mice were sacrificed on day 33, the xenograft tumors were dissected and total protein was extracted for western blot analysis. The results of the present study demonstrated that Tan-IIA inhibited the growth of BxPC-3-derived xenograft tumors. In addition, Tan-IIA increased the protein expression levels of PERK, ATF6, caspase-12, inositol-requiring enzyme (IRE) 1a, eukaryotic initiation factor (eIF) 2 alpha, phosphorylated (p)-c-Jun N-terminal kinase (JNK), CHOP and caspase-3 in a dose-dependent manner. These results indicated that Tan-IIA induced ER stress via increasing the protein expression levels of PERK, ATF6, caspase-12, IRE1 alpha, eIF2 alpha, p-JNK, CHOP and caspase-3 in BxPC-3 cells in vivo. Therefore, it may be hypothesized that Tan-IIA has potential for the development of novel therapeutic strategies for the treatment of patients with pancreatic cancer.