Targeting survivin in cancer therapy: fulfilled promises and open questions

Pennati, Marzia; Folini, Marco; Zaffaroni, Nadia

doi:10.1093/carcin/bgm047

Cited by 211 publications

(169 citation statements)

References 120 publications

(110 reference statements)

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“…The precise mechanisms underlying the cytoprotective functions of survivin remain to be fully elucidated, however, its cytoplasmic localization provides an opportunity for direct or indirect effects on components of the apoptotic machinery (Dohi et al, 2004;Arora et al, 2007). The cytoprotective function of survivin may account for the inverse correlation between the abundance of survivin in tumor cells and patient response to chemotherapy and radiotherapy (reviewed in Pennati et al, 2007). Elevated levels of survivin in tumor cells positively correlate with various indicators of aggressive disease and shorter disease-free or overall survival.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of survivin during immortalization of nontransformed human fibroblasts transduced with telomerase reverse transcriptase

et al. 2009

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These investigations demonstrate that expression of the inhibitor of apoptosis family member, survivin, is dramatically increased during immortalization of nontransformed human fibroblasts that were transduced with telomerase reverse transcriptase (hTERT). Expression of survivin in immortalized fibroblasts peaked during G 2 /M phase of the cell cycle. However, the upregulation of survivin was dissociated from the rate of proliferation and proportion of G 2 /M cells. Depletion of survivin from immortal fibroblasts increased sensitivity to stress-induced apoptosis and resulted in an accumulation of cells with 4N DNA content. Conversely, overexpression of survivin in mortal fibroblasts conferred resistance to apoptosis. In contrast, very low levels of survivin in proliferating parental fibroblasts had no bearing on sensitivity to apoptosis. The upregulation of survivin did not appear to be a direct consequence of hTERT transduction. However, repression of hTERT resulted in the rapid downregulation of survivin in telomerase-immortalized fibroblasts and tumor cell lines, but not in cells immortalized via an Alternative Lengthening of Telomeres mechanism. These results have important therapeutic implications, as telomerase and survivin are both broadly expressed in human cancers. Selection during the immortalization process for cells expressing high levels of survivin may account for the abundance of survivin in diverse tumor types.

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Section: Introductionmentioning

confidence: 99%

Upregulation of survivin during immortalization of nontransformed human fibroblasts transduced with telomerase reverse transcriptase

et al. 2009

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“…Similar to these observations, the present study, to the best of our knowledge, has demonstrated for the first time that the overexpression of survivin is capable of enhancing cell invasion in the SW620 and HCT-116 colon carcinoma cell lines. Studies performed with the use of chemically synthesized siRNAs or plasmid/viral vectors encoding shRNAs have suggested that RNAi-mediated survivin knockdown is able to suppress cancer cell proliferation and promote caspase-dependent apoptosis in a number of human tumor cell models (24). Studies from our laboratory and findings of other studies have demonstrated that inhibition of survivin using shRNA and siRNA influences the biological features of colorectal carcinoma cells and inhibits invasion and metastasis of the human colon carcinoma cell line SW480 in vitro (5,25).…”

Section: Discussionmentioning

confidence: 99%

Survivin promotes the invasion of human colon carcinoma cells by regulating the expression of MMP-7

Gao

Zhang

Yang

et al. 2014

Molecular Medicine Reports

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Abstract. Increased expression levels of survivin are crucial for invasion activity in several types of human cancer, including colon carcinoma. However, the molecular mechanisms whereby survivin regulates cancer invasion have not been completely elucidated. To the best of our knowledge, this study is the first to investigate the role of matrix metalloprotease-7 (MMP-7) in cell invasion that is induced by survivin by using in vitro assays, including western blot, immunofluorescence and qPCR analyses. The results demonstrated that the ectopic expression of survivin significantly promoted the invasive activity of colon carcinoma cells (SW620 and HCT-116) and resulted in increased levels of MMP-7 activation. By contrast, the small interfering RNA (siRNA)-based knockdown of survivin markedly reduced cell migration and led to a dose-dependent decrease in MMP-7 expression levels. Compared with the controls, knockdown of MMP-7 by siRNA in colon carcinoma cells led to reduced invasion ability, whereas no obvious changes were observed when MMP-7 expression was silenced in survivin-overexpressing colon carcinoma cells. These findings demonstrate that MMP-7 is crucial for survivin-mediated invasiveness, suggesting that the survivin-mediated MMP-7 signaling pathway is a potential therapeutic target for the treatment of colon carcinoma. IntroductionSurvivin, a member of the family of inhibitor of apoptosis (IAP) proteins, contains 142 amino acid residues. Survivin functions as a key regulator of mitosis and programmed cell death by inhibiting apoptosis and promoting cell proliferation (1). Studies have identified that survivin is able to promote the migratory/invasive properties of several types of human cancer, including melanoma, prostate cancer and breast cancer (2-4). Survivin has been demonstrated to regulate the invasion ability of colorectal cancer (CRC) (5,6). However, little is known regarding the functional mechanism of survivin in CRC invasion. A better understanding of the mechanisms by which survivin regulates aggressive cellular behaviors may lead to the production of novel therapeutic targets for colon cancer.The extracellular matrix (ECM) provides a structural framework to support cells and maintains cell functions by mediating cell-cell or cell-ECM interactions. Degradation of ECM components is mainly controlled by matrix metalloproteinases (MMPs), a large group of enzymes (7). The MMPs comprise a family of zinc-dependent endopeptidases that consist of >21 human proteases and are important in carcinogenesis. One of the smallest known members of the MMP family, MMP-7, was first identified as an enzyme of the involuting rat uterus and was subsequently determined to be an important marker in human cancer progression (8). For example, MMP-7 has been reported to be overexpressed in numerous types of human malignancy, including ovarian, prostate, gastric and breast cancer (9-12), and is important in cancer progression as it promotes tumor invasion. Furthermore, the ability of CRC cells to migrate and invade has be...

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“…Besides BIRC5 gene-targeting therapy, smallmolecule inhibitors of survivin expression are under investigation in this context (30). There are several mechanisms whereby small molecules inhibit survivin expression in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

(-)-Epigallocatechin-3-gallate induces apoptosis in gastric cancer cell lines by down-regulating survivin expression

Onoda

Kuribayashi²,

Nirasawa³

et al. 2011

Int J Oncol

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Abstract. The polyphenol (-)-epigallocatechin-3-gallate (EGCG) is a green tea constituent, which has been shown to inhibit cancer cell growth in vitro, in vivo and in epidemiological studies. In this study, we investigated its effects in gastric cancer cell lines. Five gastric cancer cell lines, the MKN-1, MKN-28, MKN-45, NUGC-3 and TMK-1, were found to be sensitive to EGCG treatment. Of all the cell lines tested, NUGC-3 was the most sensitive. EGCG treatment of NUGC-3 cells induced apoptosis, which was confirmed by sub-G1 analysis, caspase-Glo assay and Western blotting against cleaved PARP and cleaved caspase-3. EGCG treatment lowered survivin and increased Bax and TRAIL expression. Furthermore, EGCG induced p73 activation in NUGC-3 cells. Small interfering RNA against p73 diminished EGCG effects on survivin expression and cell viability. These results show that EGCG induces cell death in gastric cancer cells by apoptosis via inhibition of survivin expression downstream of p73. This study provides a novel mechanism whereby EGCG potentially inhibits cancer cell growth, concluding that EGCG may be a potential candidate in anti-survivin cancer therapy.

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Targeting survivin in cancer therapy: fulfilled promises and open questions

Cited by 211 publications

References 120 publications

Upregulation of survivin during immortalization of nontransformed human fibroblasts transduced with telomerase reverse transcriptase

Upregulation of survivin during immortalization of nontransformed human fibroblasts transduced with telomerase reverse transcriptase

Survivin promotes the invasion of human colon carcinoma cells by regulating the expression of MMP-7

(-)-Epigallocatechin-3-gallate induces apoptosis in gastric cancer cell lines by down-regulating survivin expression

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