Shikonin inhibits prostate cancer cells metastasis by reducing matrix metalloproteinase-2/-9 expression via AKT/mTOR and ROS/ERK1/2 pathways

Chen, Yongqiang; Zheng, Lu; Liu, Junquan; Zhou, Zhonghai; Cao, Xiaohong; Lv, Xiaoting; Chen, Fuxing

doi:10.1016/j.intimp.2014.05.026

Cited by 78 publications

(52 citation statements)

References 38 publications

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“…MAPK/ERK, one classic downstream signal of the EGFR pathway, could regulate CD44 to modulate tumor aggressiveness (38). The most recent study showed that prostate cancer cell migration and invasion were inhibited by reducing MMP-2/-9 expression via the ROS/ERK pathways (39). Based on this evidence and our present results, it seems reasonable to conclude that ASPN regulates gastric cancer metastasis through activation of EGFR and the ERK-CD44/MMP-2 pathway.…”

Section: Discussionsupporting

confidence: 76%

Asporin participates in gastric cancer cell growth and migration by influencing EGF receptor signaling

2015

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Abstract. Asporin (ASPN), a novel member of the small leucine-rich proteoglycan (SLRP) family, serves as a key component of the tumor stroma and has been reported to be abnormally expressed in certain types of tumors. Specifically, the proteoglycan was proven to activate the coordinated invasion of scirrhous gastric cancer and cancer-associated fibroblasts. However, the role of ASPN in cancer cell growth and metastasis has not yet been addressed. In the present study, we aimed to evaluate the tumoricidal benefits of ASPN on tumorigenesis and progression of gastric cancer. Firstly, it was demonstrated that ASPN was overexpressed in gastric carcinoma tissues when compared to the corresponding non-cancerous tissues, and it had varied levels of expression in gastric cancer epithelial cell lines. Additionally, we assessed the effects of transient siRNA-mediated ASPN knockdown on gastric cancer cells. ASPN silencing inhibited proliferation and suppressed the migration of immortalized neoplastic epithelial cells. Furthermore, at the molecular level, we found that downregulation of ASPN blocked the anti-apoptotic molecule Bcl-2, increased the expression of pro-apoptotic molecule Bad, reduced the expression of migration-related proteins CD44 and matrix metalloproteinase (MMP)-2, and abrogated the activation of the phosphorylation status of ERK and epidermal growth factor (EGF) and its receptor (EGFR). Collectively, our findings indicate that ASPN is upregulated and plays an oncogenic role in gastric cancer progression and metastasis by influencing the EGFR signaling pathway.

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Section: Discussionsupporting

confidence: 76%

Asporin participates in gastric cancer cell growth and migration by influencing EGF receptor signaling

2015

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“…Following the above observations, the question concerning how SFN regulated MMP-2 expression and activity is raised. One possible mechanism leading to decreased MMP-2 may be that SFN activates or inactivates some transcription factors, such as nuclear factor-кB (NF-кB), SNaIl and ZEB (30,53). In addition, MMPs can also be regulated by their endogenous tissue inhibitors TIMPs, and the proteolytic activity of tumor cells depends on the balance between MMPs and TIMPs (47).…”

Section: Discussionmentioning

confidence: 99%

Sulforaphane inhibits invasion by phosphorylating ERK1/2 to regulate E-cadherin and CD44v6 in human prostate cancer DU145 cells

et al. 2015

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Abstract. Advanced prostate cancer has highly invasive potential, which may lead to metastasis associated with poor prognosis. Sulforaphane (SFN), abundant in cruciferous vegetables, exhibited effective resistance to carcinogenesis in a variety of tumors. The aim of the present study was to investigate whether SFN inhibited invasion in human prostate cancer cells via sustained activation of ERK1/2 and downstream signaling by an invasion assay, gelatin zymography and western blot analysis. The results showed that SFN inhibited invasion and we characterized the underlying mechanisms in human DU145 prostate cancer cells. SFN (15 µM) changed cell morphology leading to short-cell pseudopodia which may suppress tumor migration and invasion. The Transwell assay showed that SFN phosphorylated ERK1/2 in a doseand time-dependent manner and significantly inhibited cell invasion, while the effect was reduced by the ERK1/2 blocker PD98059 (25 µM). Furthermore, these effects contributed to the upregulation of E-cadherin and the downregulation of CD44v6 and were eradicated by PD98059. Western blot analysis and gelatin zymography showed that SFN decreased the expression and activity of MMP-2. Thus, SFN inhibited invasion by activating ERK1/2 to upregulate E-cadherin and downregulate CD44v6, thereby reducing MMP-2 expression and activity. E-cadherin is an invasion inhibitor, while CD44v6 and MMP-2 are invasion promoters. Therefore, SFN is a prospective therapeutic agent that may be used to prevent invasion in prostate cancer.

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“…Recently numerous studies have illustrated that shikonin held anti-cancer potential in various cancers, including lung, colon, breast, osteosarcoma cancer and acute myeloid leukemia [9-13]. Shikonin inhibited the metastasis of cancer cells by suppressing matrix metalloproteinase-2/-9 expression as well as matrix metalloproteinase-13 [14-16]. LPS-induced epithelial mesenchymal transition (EMT) was reduced by shikonin via inactivation of NF-κB signaling pathway [17].…”

Section: Introductionmentioning

confidence: 99%

TRAIL Enhances Shikonin Induced Apoptosis through ROS/JNK Signaling in Cholangiocarcinoma Cells

Zhou

Yang

Wang

et al. 2017

Cell Physiol Biochem

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Background/Aims: Cholangiocarcinoma (CCA), arising from varying locations within the biliary tree, is the second most common primary liver malignancy worldwide. Shikonin, an active compound extracted from the Chinese herb Zicao, holds anti-bacterial, anti-inflammatory, and anti-tumor activities. However, the effect of shikonin on human cholangiocarcinoma and detailed mechanisms of TRAIL enhancement remains to be elucidated. The purpose of the study was to investigate the protective functions of TRAIL enhancement for shikonin induced apoptosis in cholangiocarcinoma cells. Methods: We use MTT assay, apoptosis assay, caspase activity assay, flow cytometry assay, real time PCR and Western blot to observe the effects of TRAIL on shikonin induced cholangiocarcinoma cells apoptosis and its mechanism. Results: Shikonin inhibited cell viability and induced apoptosis of CCA cells, effects enhanced by TRAIL treatment via activation of caspase-3, -8, -9. Furhermore, TRAIL enhanced anti-proliferation of shikonin and shikonin induced apoptosis through induction of ROS mediated JNK activation, while AKT activation had an effect on shikonin anti-proliferation activity, but not in the TRAIL enhanced counterparts. Finally, shikonin upregulated DR5 expression, an effect essential for TRAIL-enhanced activities of shikonin in RBE cells. Conclusions: Our results revealed that shikonin could inhibit cells viability and induce apoptosis of CCA cells, effects enhanced by TRAIL treatment via ROS mediated JNK signalling pathways, involving up-regulation of DR5 expression. Our results provide further insight into the mechanism underlying the anti-tumor effects of shikonin by TRAIL enhanced in CCA and a new therapeutic strategy to CCA treatment.

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Shikonin inhibits prostate cancer cells metastasis by reducing matrix metalloproteinase-2/-9 expression via AKT/mTOR and ROS/ERK1/2 pathways

Cited by 78 publications

References 38 publications

Asporin participates in gastric cancer cell growth and migration by influencing EGF receptor signaling

Asporin participates in gastric cancer cell growth and migration by influencing EGF receptor signaling

Sulforaphane inhibits invasion by phosphorylating ERK1/2 to regulate E-cadherin and CD44v6 in human prostate cancer DU145 cells

TRAIL Enhances Shikonin Induced Apoptosis through ROS/JNK Signaling in Cholangiocarcinoma Cells

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