Proteomic analysis reveals tanshinone <scp>IIA</scp> enhances apoptosis of advanced cervix carcinoma <scp>C</scp>a<scp>S</scp>ki cells through mitochondria intrinsic and endoplasmic reticulum stress pathways

Pan, Tai‐Long; Wang, Pei‐Wen; Hung, Yu‐Chiang; Huang, Chih‐Fen; Rau, Kun‐Ming

doi:10.1002/pmic.201300274

Cited by 41 publications

(25 citation statements)

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“…When the unfolded protein response exceeds a threshold, damaged cells become apoptotic, through a mechanism that may involve the caspase-12-and ATF6-mediated induction of the CHOP signaling pathway (14,15). Pan et al reported that Tan-IIA may enhance the apoptosis of CaSki advanced cervical carcinoma cells, through the activation of intrinsic mitochondrial and ER stress-associated pathways (16). In addition, Chiu et al demonstrated that Tan-IIA inhibited the growth of human prostate cancer cells through the induction of ER stress in vitro and in vivo (17).…”

Section: Discussionmentioning

confidence: 99%

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

Chiu

2017

Molecular Medicine Reports

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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.

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Section: Discussionmentioning

confidence: 99%

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

Chiu

2017

Molecular Medicine Reports

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“…Studies in the past decade suggest that TSIIA hits the model of 'one-drug-multi-target-multi-disease', which is shared by traditional Chinese medicines (TCM), such as berberine (44). TSIIA (15) and CaSki (17). However, the precise mechanism of the antitumor activity of TSIIA has remained unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have suggested that CTS mainly inhibited angiogenesis (3), while TSI mainly inhibited migration, invasion and metastasis (4). Whereas, TSIIA significantly induced cell apoptosis on a panel of human tumor cell lines, such as breast cancer (5)(6)(7), glioma (8), lung cancer (9,10), ovarian cancer (11), gastric cancer (12), hepatoma (13), leukemia (14), prostate cancer (15), renal cell carcinoma (16), cervix carcinoma (17) and colon cancer (18). Therefore, TSIIA might have therapeutic potential in cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

Tanshinone IIA induces cytochrome c-mediated caspase cascade apoptosis in A549 human lung cancer cells via the JNK pathway

Zhang

Wang

Jiang

et al. 2014

International Journal of Oncology

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Tanshinone IIA (TSIIA), a natural diterpene quinone in the traditional Chinese medicinal herb Dan-Shen (Salvia miltiorrhiza), has extensively exerted antitumor activity in cellular and animal models. However, the molecular mechanisms underlying the antitumor effects of TSIIA remain largely unknown. The in vitro effects of TSIIA on apoptosis were investigated in A549 non-small cell lung cancer (NSCLC) cells. The data showed that TSIIA significantly suppressed the proliferation of A549 cells in a dose-dependent manner, with IC50 values of 16.0±3.7 and 14.5±3.3 µM at 48 h as determined by Cell Counting Kit-8 (CCK-8) assay and clone formation assay, respectively. The change of mitochondrial morphology and the loss of mitochondrial membrane potential (MMP) were observed during the induction. Furthermore, TSIIA induced A549 cell apoptosis as confirmed by typical morphological changes, with cytochrome c release from the mitochondria and Bax translocation to the mitochondria. Caspase activity data indicated that TSIIA activated caspase-9 and caspase-3 of mitochondria-mediated apoptosis, but not caspase-8 of receptor-mediated apoptosis, which could be largely rescued by SP600125 (JNK inhibitor). Taken together, these findings provide the first evidence that TSIIA inhibits growth of NSCLC A549 cells, induces activation of JNK signaling and triggers caspase cascade apoptosis mediated by the release of cytochrome c, which provides a better understanding of the molecular mechanisms of TSIIA on lung cancer.

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“…Both mitochondria‐independent and ERS pathways may participate in the molecular mechanism of Eca‐109 cell apoptosis, thus providing support for the application of Tan IIA for treatment of esophageal carcinoma. In addition, some studies have reported that there might be cross‐talk between these two pathways; however, the detailed mechanism still requires further study. Our study provides a basis for further clarification of the apoptosis mechanism and exploration of the anti‐tumor therapy effects of traditional Chinese medicine.…”

Section: Discussionmentioning

confidence: 99%

Influence of Tanshinone IIA on apoptosis of human esophageal carcinoma Eca‐109 cells and its molecular mechanism

Zhang

et al. 2017

Thoracic Cancer

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BackgroundPrevious studies have shown that Tanshinone (Tan) IIA exerts obvious antitumor efficacy; however, its molecular mechanism remains unclear. This study was conducted to identify the influence of Tan IIA on Eca‐109 cell apoptosis, explore its molecular mechanism, and provide a theoretical basis for clinical application.MethodsEca‐109 cells were cultured in vitro and treated with different concentrations of Tan IIA. Morphologic changes were viewed under inverted fluorescence microscope with dual acridine orange/ethidium bromide staining assay. Methyl‐thiazolyl‐tetrazolium and Annexin V propidium iodide assays were respectively used to measure cell viability and apoptosis rate. The protein and messenger (m)RNA expression of binding immunoglobulin protein (BIP), mitochondrial cytochrome c (CytC), and caspase‐9 were detected by Western blot and quantitative real‐time PCR, respectively.ResultsCell viability decreased and the apoptosis rate significantly increased with increasing concentrations of Tan IIA (0, 20, 40, 60 μg/mL), which indicated that Tan IIA inhibited the proliferation and induced the apoptosis of Eca‐109 cells in a dose‐dependent manner. Eca‐109 cells treated with 60 μg/mLTan IIA showed typical morphological changes of apoptosis under the inverted microscope. Moreover, compared with the negative control group, protein and mRNA expression of BIP decreased significantly (P < 0.05), whereas protein and mRNA expression of CytC and caspase‐9 increased significantly (P < 0.05).ConclusionTan IIA can induce apoptosis in human esophageal carcinoma Eca‐109 cells by regulating BIP, CytC, and caspase‐9 expression. Endoplasmic reticulum stress and mitochondrial‐dependent may be involved in Tan IIA‐induced Eca‐109 cell apoptosis.

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Proteomic analysis reveals tanshinone IIA enhances apoptosis of advanced cervix carcinoma CaSki cells through mitochondria intrinsic and endoplasmic reticulum stress pathways

Cited by 41 publications

References 42 publications

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

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

Tanshinone IIA induces cytochrome c-mediated caspase cascade apoptosis in A549 human lung cancer cells via the JNK pathway

Influence of Tanshinone IIA on apoptosis of human esophageal carcinoma Eca‐109 cells and its molecular mechanism

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