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Ching-Fong Liao,
Shu-Hui Lin,
Hung-Chang Chen,
Cheng-Jeng Tai,
Chun-Chao Chang,
Li-Tzu Li,
Chung-Min Yeh,
Kun-Tu Yeh,
Ying-Chun Chen,
Tsu-Han Hsu,
Shing-Chuan Shen,
Woan-Ruoh Lee,
Jeng-Fong Chiou, Shue-Fen Luo,
Ming-Chung Jiang
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ABSTRACT: Tumor-derived microvesicles are rich in metastasis-related proteases and play a role in the interactions between tumor cells and tumor microenvironment in tumor metastasis. Because shed microvesicles may remain in the extracellular environment around tumor cells; the microvesicle membrane protein may be the potential target for cancer therapy. Here we report that CSE1L is a microvesicle membrane protein and is a potential target for cancer therapy. v-H-Ras expression induced ERK-dependent CSE1L phosphorylation and microvesicle biogenesis in various cancer cells. CSE1L overexpression also triggered microvesicle generation and CSE1L knockdown diminished v-H-Ras-induced microvesicle generation, matrix metalloproteinases MMP-2 and MMP-9 secretion, and metastasis of B16F10 melanoma cells. CSE1L was preferentially accumulated in microvesicles and was located in the microvesicle membrane. Furthermore, anti-CSE1L antibodies-conjugated quantum dots could target tumor in animal models. Our findings highlight a novel role of Ras-ERK signaling in tumor progression and suggest that CSE1L may be involved in the "early" and "late" metastasis of tumor cells in tumourigenesis. Furthermore, the novel microvesicle membrane protein, CSE1L, may have clinical utility in cancer diagnosis and targeted cancer therapy.
Molecular Medicine 08/2012; · 3.76 Impact Factor
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ABSTRACT: Epidemiological studies indicate that acetylsalicylic acid may reduce the risk of mortality due to colon cancers. Metastasis is the major cause of cancer death. Matrix metalloproteinases (MMPs) play important roles in tumor invasion regulation, and prostaglandin F(2)alpha (PGF(2)alpha) is a key stimulator of MMP production. Thus, we investigated whether acetylsalicylic acid regulated MMP activity and the invasion of cancer cells and whether PGF(2)alpha attenuated acetylsalicylic acid-inhibited invasion of cancer cells. Gelatin-based zymography assays showed that acetylsalicylic acid inhibited the MMP-2 activity of B16F0 melanoma cells. Matrigel-based chemoinvasion assays showed that acetylsalicylic acid inhibited the invasion of B16F0 cells. Acetylsalicylic acid can inhibit PGF(2)alpha synthesis and PGF(2)alpha is a key stimulator of MMP-2 production. Our data showed that PGF(2)alpha treatment attenuated the acetylsalicylic acid-inhibited invasion of B16F0 cells. In animal experiments, acetylsalicylic acid reduced colorectal metastasis of B16F0 cells in C57BL/6J mice by 44%. Our results suggest that PGF(2)alpha is a therapeutic target for metastasis inhibition and acetylsalicylic acid may possess anti-metastasis ability.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 10/2008; 63(7):522-7. · 2.24 Impact Factor
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ABSTRACT: The cellular apoptosis susceptibility (CAS) protein is regarded as a proliferation-associated protein that associates with tumour proliferation as it associates with microtubule and functions in the mitotic spindle checkpoint. However, there is no any actual experimental study showing CAS (or CSE1 and CSE1L) can increase the proliferation of cancer cells. Previous pathological study has reported that CAS was strongly positive stained in all of the metastasis melanoma that be examined. Thus, CAS may regulate the invasion and metastasis of cancers. CAS is highly expressed in cancers; if CAS is associated with cancer proliferation, then increased CAS expression should be able to increase the proliferation of cancer cells. We studied whether increased CAS expression can increase cancer cell proliferation and whether CAS regulates the invasion of cancer cells.
We enhanced or reduced CAS expression by transfecting CAS or anti-CAS expression vectors into human MCF-7 breast cancer cells. The proliferations of cells were determined by trypan blue exclusion assay and flow cytometry analysis. Invasion of cancer cells were determined by matrigel-based invasion assay.
Our studies showed that increased CAS expression was unable to enhance cancer cell proliferation. Immunofluorescence showed CAS was distributed in cytoplasm areas near cell membrane and cell protrusions. CAS was localized in cytoplasmic vesicle and immunogold electronmicroscopy showed CAS was located in vesicle membrane. CAS overexpression enhanced matrix metalloproteinase-2 (MMP-2) secretion and cancer cell invasion. Animal experiments showed CAS reduction inhibited the metastasis of B16-F10 melanoma cells by 56% in C57BL/6 mice.
Our results indicate that CAS increases the invasion but not the proliferation of cancer cells. Thus, CAS plus ECM-degradation proteinases may be used as the markers for predicting the advance of tumour metastasis.
Journal of Experimental & Clinical Cancer Research 04/2008; 27:15. · 2.15 Impact Factor
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ABSTRACT: CSE1L/CAS, a microtubule-associated, cellular apoptosis susceptibility protein, is highly expressed in various cancers. Microtubules are the target of paclitaxel-induced apoptosis. We studied the effects of increased or reduced CAS expression on cancer cell apoptosis induced by chemotherapeutic drugs including paclitaxel. Our results showed that CAS overexpression enhanced apoptosis induced by doxorubicin, 5-fluorouracil, cisplatin, and tamoxifen, but inhibited paclitaxel-induced apoptosis of cancer cells. Reductions in CAS produced opposite results. CAS overexpression enhanced p53 accumulation induced by doxorubicin, 5-fluorouracil, cisplatin, tamoxifen, and etoposide. CAS was associated with alpha-tubulin and beta-tubulin and enhanced the association between alpha-tubulin and beta-tubulin. Paclitaxel can induce G2/M phase cell cycle arrest and microtubule aster formation during apoptosis induction, but CAS overexpression reduced paclitaxel-induced G2/M phase cell cycle arrest and microtubule aster formation. Our results indicate that CAS may play an important role in regulating the cytotoxicities of chemotherapeutic drugs used in cancer chemotherapy against cancer cells.
BMB reports 04/2008; 41(3):210-6. · 1.72 Impact Factor
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ABSTRACT: ABSTRACT Cells attacked by cytotoxic toxins may express apoptosis-related proteins such as p53 to kill themselves, so as not to affect surrounding healthy cells. These apoptosis-related proteins are also crucial for inducing apoptosis of tumor cells in cancer chemotherapy. CSE1L/CAS is a cellular apoptosis susceptibility protein that plays important roles in mediating cell apoptosis induced by various cytotoxic toxins and chemotherapeutic drugs. Our studies showed that CAS over-expression increased p53 accumulation and apoptosis induced by 5-fluorouracil, doxorubicin, cisplatin, and tamoxifen in HT-29 cancer cells. A method based on coexpression of CAS with green fluorescence protein (GFP) was developed for high-sensitivity anticancer drug screening. Cancer cells transfected with CAS- and GFP-expressing vectors or the control and GFP-expressing vectors were grown on 96-well microplates, treated with compounds to be screened, and detected with a microplate fluorescence reader. GFP fluorescence decreased following cancer cell death induced by the anticancer compounds. CAS transfection enhanced the cytotoxicities of anticancer compounds and therefore increased the decline in GFP fluorescence. Thus, anticancer compounds could be identified more sensitively. Our study indicates that CAS is an important p53 and apoptosis regulator and may be used for high-throughput anticancer drug screening as well as cytotoxic toxin assays.
Toxicology mechanisms and methods 01/2008; 18(9):771-6. · 1.03 Impact Factor
