Tanshinone IIA increases protein expression levels of PERK, ATF6, IRE1α, CHOP, caspase-3 and caspase-12 in pancreatic cancer BxPC-3 cell-derived xenograft tumors

Abstract

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 (2x106/0.2 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) 1α, eukaryotic initiation factor (eIF) 2α, 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, IRE1α, eIF2α, 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.

Tanshinone IIA induces apoptosis of ovarian cancer cells in�vitro and in�vivo through attenuation of PI3K/AKT/JNK signaling pathways

“…A previous study demonstrated that Tan-IIA inhibited BxPC3-derived xenograft tumor growth by increasing the protein expression levels of PKR-like endoplasmic reticulum kinase, activating transcription factor 6, inositol-requiring enzyme 1α, CCAAT-enhancer-binding protein homologous protein, caspase 3 and caspase 12 (21). The results of the present study showed that Tan-IIA inhibited ovarian tumor growth by inducing apoptosis through the regulation of apoptosis-associated protein expression.…”

The Anticancer Properties of Tanshinones and the Pharmacological Effects of Their Active Ingredients

“…Sustained ER stress activates protein interacting with C-kinase (PICK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6), leading to the activation of the proapoptotic factor C/EBP homologous protein (CHOP), which further promotes the activation of caspase-dependent apoptosis . Previously, Tan IIA increased expression of protein kinase RNA-like ER kinase (PERK), ATF6, inositolrequiring enzyme 1α (IRE1α), caspase-12, and downstream eukaryotic initiation factor 2α (eIF2α), phosphorylated c-Jun N-terminal kinase (p-JNK), and CHOP to activate ER-mediated apoptosis in human pancreatic cancer BxPC-3 cells in vitro (Chiu and Su, 2017). Tan IIA also induced ER stress and apoptosis in human breast cancer BT-20 cells by increasing caspase-12, DNA damage-inducible gene 153 (GADD153), caspase-3, p-JNK, phospho-p38 mitogen-activated protein kinases (p-p38), and Bcl-2-Associated X protein (Bax) levels with decreased expression of B-cell lymphoma extra large (Bcl-xl) and p-ERK in a time-and dose-dependent manner (Yan et al, 2012).…”

“…In gastric cancer AGS cell xenograft SCID mice model, results showed that treatment with Tan IIA for 8 weeks significantly reduced the protein expression levels of epidermal growth factor receptor (EGFR), inverted gravity flame reactor (IGFR), PI3K, AKT, and mTOR and inhibited AGS cell proliferation by blocking the PI3K/AKT/mTOR pathway (Su and Chiu, 2016). In BxPC-3-derived xenograft tumor model, treatment with Tan IIA induced ER stress by up-regulating the levels of PERK, ATF6, caspase-12, IRE1α, eIF2α, p-JNK, CHOP, and caspase-3 and inhibited the tumor growth in vivo (Chiu and Su, 2017).…”

Effect and mechanisms of celastrol on the apoptosis of HOS osteosarcoma cells

“…To suppress the protective function of ERS, further promote apoptosis and enhance the chemotherapeutic effect of celastrol, we sought to reverse the target of HOS-cell resistance to celastrol. Studies have found that PERK is the key factor of the PERK/EIF2α signaling pathway (33,34). Salaroglio et al (13) reported that PERK molecules mediated colon cancer cell resistance to ERS and chemotherapeutic agents.…”