P-0031 - Tanshinone IIA can inhibit human pancreatic cancer BxPC-3 cells through inducing endoplasmic reticulum stress
|Date||28 June 2014|
|Event||World GI 2014|
|Topics|| Basic Science
|Presenter||Cheng Su Chin|
|Citation||Annals of Oncology (2014) 25 (suppl_2): ii14-ii104. 10.1093/annonc/mdu165|
C. Su Chin
Tanshinone IIA (C19H18O3) is one of the active components in Radix Salviae miltiorrhizae. It was well documented that Tanshinone IIA (Tan-IIA) has anti-inflammatory activities and antioxidant properties. In our previous studies showed that Tan-IIA can inhibit many human cancer cell lines through different molecular mechanisms, such as Tan-IIA down-regulates ErbB-2 and up-regulates TNF-alpha expression to inhibit colon cancer colo205 cells, Tan-IIA inhibits human breast cancer MDA-MB-231 cells through increasing Bax to Bcl-xL ratios, Tan-IIA inhibits human non-small cell lung cancer A549 cells through the induction of reactive oxygen species and decreasing the mitochondrial membrane potential. Pancreatic cancer is a challenging disease in worldwide. In 2012, pancreatic cancer is the 4th leading cause of cancer death in the U.S.A. Gemcitabine is the standard treatment for pancreatic cancer patients, but the survival rate for one year was only 18%. Although many efforts have been made to improve the clinical efficacy, but current chemotherapeutic medicines for pancreatic cancer are unsatisfactory and need to identify new treatments. Tan-IIA possesses cytotoxic effects in human pancreatic (MIAPaCa-2) tumor cell lines was documented, but the mechanism has not been established. Our previous study showed that Tan-IIA can inhibit human pancreatic cancer BxPC-3 cells through decreasing TCTP, Mcl-1 and Bcl-xl expression. It was well documented that Tan- IIA could inhibit hepatocellular carcinoma Hep-J5 cells and breast cancer BT-20 cells through inducing ER stress. In the present study, we investigated the ER stress related protein expressions in human pancreatic cancer BxPC3 cells were treated with Tan-IIA.
The cytotoxicity of Tan-IIA in human pancreatic cancer BxPC-3 cells was measured by MTT assay. The ER-stress-related protein expressions (such as: Bip, PDI, Calnexin, Calreticulin, IRE1α, PERK, elF2α, ATF6, ATF4, Caspase-12, Caspase-9 and CHOP) in BxPC-3 cells were evaluated by western blotting. The protein expression of Caspase-3 in BxPC-3 cells were treated with Tan-IIA was observed by Immunocytochemistry.
The results showed that Tan-IIA can inhibit the proliferation of BxPC-3 cells with time and dose dependent. Tan-IIA down regulated the proteins expression of Bip, PDI, Calnexin, Calreticulin and Bcl-2 but up regulated the proteins expression of PERK, ATF6, Caspase-12 and CHOP. The I.C.C results showed that BxPC-3 cells were treated with Tan-IIA can increase the Caspase-3 expression with dose dependent.
These findings suggested that Tan-IIA can inhibit the proliferations of human pancreatic cancer BxPC-3 cells through ER stress to induce apoptosis. The proposed molecular mechanisms for Tan-IIA to inhibit BxPC-3 cells as follow: Tan-IIA induce UPR through decreasing the protein expression of Bip, PDI, Calnexin and Calreticulin, then increase PERK, elF2α, ATF4, IRE1α, Caspase-12 and ATF6 expression and then stimuli ER stress downstream CHOP over expression. In addition, CHOP decreased Bcl-2 protein expression and induced mitochondria dysfunction to induce apoptosis. This is the first report. Tan-IIA with chemotherapeutic potential for human pancreatic cancer BxPC-3 cells in vitro. It is warrants further study in vivo.