Survivin beyond physiology: Orchestration of multistep carcinogenesis and therapeutic potentials

Athanasoula, Kalliopi Ch.; Gogas, Helen; Polonifi, Katerina; Vaiopoulos, Aristeidis G.; Polyzos, Aristidis; Mantzourani, Marina

doi:10.1016/j.canlet.2014.02.014

Cited by 58 publications

(51 citation statements)

References 95 publications

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“…16,17 Moreover, survivin is highly-expressed in a plethora of human malignancies but absent in normal cell. 15 These characteristics suggest that survivin may likely be a possible mediator of the above-mentioned underlying mechanism. Hence, we explored the role of survivin in metformin-induced apoptosis.…”

Section: Resultsmentioning

confidence: 99%

“…15 Survivin inhibits apoptosis and protects cancerous cell against various cytotoxic factors, thus conferring immortalization and immune privilege to cancer cell. 16,17 Moreover, survivin is highly-expressed in a plethora of human malignancies but absent in normal cell.…”

Section: Resultsmentioning

confidence: 99%

“…20 Based on the aforementioned finding, we went on exploring the underlying mechanism. Considering survivin is an inhibitor against apoptosis and only highly-expressed in a variety of cancers, 15 we thus evaluated the involvement of survivin in metformin-induced apoptosis of gastric cancer cell, and found that metformin-induced apoptosis may be mediated, at least in part, by inhibition of survivin expression. Interestingly, as revealed in Figure 2, metformin-induced decrement of survivin expression seems to associate negatively with the differentiation degree of gastric cancer, which also coincides well with the negative correlation between the apoptotic effect of metformin and the differentiation degree (Figs.…”

Section: Discussionmentioning

confidence: 99%

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AMPK/mTOR-mediated inhibition of survivin partly contributes to metformin-induced apoptosis in human gastric cancer cell

Hou¹,

Gong

Wang

et al. 2014

Cancer Biology & Therapy

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Recent studies demonstrated that metformin exerts anti-neoplastic effect in a spectrum of malignancies. However, the mechanism whereby metformin affects various cancers, including gastric cancer, is poorly elucidated. Considering apoptosis plays critical role in tumorigenesis, we, in the present study, investigated the in vitro apoptotic effect of metformin on human gastric cancer cell and the underlying mechanism. Three differently-differentiated gastric cancer cell lines, MKN-28, SGC-7901 and BGC-823, along with one noncancerous gastric cell line GES-1 were used. We found that metformin treatment selectively induces apoptosis in the 3 cancer cell lines, but not the noncancerous one, as confirmed by flow cytometry, Caspase-Glo assay and western blotting against PARP and cleaved caspase 3. Moreover, the apoptotic effect of metformin seems to correlate negatively with the differentiation degree of gastric cancer. Metformin-induced apoptosis may be partially mediated through inhibition of anti-apoptotic survivin. Additionally, AMPK and mTOR, 2 important regulatory molecules responsible for metformin action, were investigated for their possible involvements in metformin-induced apoptosis of gastric cancer cell. AMPK knockdown by siRNA restores metformin-inhibited survivin expression and partially abolishes metformin-induced apoptosis. Similarly, forced overexpression of mTOR downstream effector p70S6K1 relieves metformin-induced inhibition of survivin and partly attenuates metformin-induced apoptosis. More importantly, survivin overexpression alleviates metformin-induced apoptosis. Xenograft nude mouse experiment also confirmed that AMPK/mTOR-mediated decrease of suvivin is in vivo implicated in metformin-induced apoptosis. Taken together, these evidences suggest that AMPK/mTOR-mediated inhibition of survivin may partly contribute to metformin-induced apoptosis of gastric cancer cell.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

AMPK/mTOR-mediated inhibition of survivin partly contributes to metformin-induced apoptosis in human gastric cancer cell

Hou¹,

Gong

Wang

et al. 2014

Cancer Biology & Therapy

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“…Moreover, the cleaved caspase-3 protein expression increased after CENP-H knockdown based on western blotting. Survivin, a member of the inhibitor of apoptosis protein family, has been implicated as a protector against cell apoptosis; the aberrant high expression of this factor in cancers is closely correlated with advanced disease and poor overall survival (20,21). According to previous studies, CENP-H siRNA decreases the protein expression of survivin, indicating apoptosis induction (12,18).…”

Section: Discussionmentioning

confidence: 98%

CENP-H regulates the cell growth of human hepatocellular carcinoma cells through the mitochondrial apoptotic pathway

Hou

et al. 2017

Oncology Reports

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Abstract. The genomic alterations of hepatocellular carcinoma (HCC) are still unclear. Centromere protein-H (CENP-H) has been shown to be associated with many solid tumors. Our previous study found that CENP-H was upregulated in HCC and was related to patient prognosis. However, the biological functions of CENP-H in HCC and the possible underlying mechanisms have not been well elucidated. In the present study, we demonstrated that CENP-H knockdown inhibited the proliferation of Hep3B cells and decreased colony formation ability of single cells in vitro. Furthermore, CENP-H knockdown induced Hep3B cell apoptosis, and apoptotic bodies were observed using transmission electron microscopy. The protein expression of cleaved caspase-3 was upregulated in Hep3B cells after CENP-H knockdown. Additionally, a Bax/Bcl-2 ratio imbalance with a significant increase of Bax and a substantial decrease of Bcl-2 at both the mRNA and protein levels were determined in this study. In an animal experiment, CENP-H knockdown blocked the growth of Hep3B subcutaneous xenografts. Immunohistochemistry revealed that the protein expression of cleaved caspase-3 and Bax was increased, whereas the protein expression of Bcl-2 and Ki-67 was decreased in subcutaneous xenografts of the CENP-H-knockdown group. In summary, CENP-H may be involved in cell proliferation and apoptosis of HCC cells through the mitochondrial apoptotic pathway. Combined with previous studies, the data provide a new perspective on HCC development and progression.

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“…Among the caspase family, caspase-3 acts as the rate-limiting enzyme that determines the extent of apoptosis. Survivin is another important regulator of cell survival that has been demonstrated to inhibit apoptotic signals by inhibiting the activation of endogenous caspase-9 (21). Survivin has also demonstrated the ability to exert an anti-apoptotic effect through competitively binding with the p21-cdk4 complex, thereby promoting the release of p21.…”

Section: Discussionmentioning

confidence: 99%

Oxymatrine inhibits proliferation of human bladder cancer T24 cells by inducing apoptosis and cell cycle arrest

Zhang²,

Liu

et al. 2017

Oncology Letters

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Abstract.Oxymatrine has been shown to exert an antitumor effect on several types of cancer cells. However, the role of oxymatrine in bladder cancer has not yet been evaluated. The present study was designed to investigate the potential anti-proliferative effect of oxymatrine on bladder cancer T24 cells and the possible mechanisms involved. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to determine cell growth, and the cell morphology was examined using hematoxylin and eosin staining, wrights' staining and electron microscopy. The caspase-3 and survivin mRNA and protein levels were assessed using reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. The expression of tumor protein p53 (p53), Bcl-2-associated X protein (Bax) and B-cell lymphoma 2 (Bcl-2) were analyzed using immunohistochemistry. Oxymatrine inhibited the proliferation of the T24 cells in a dose-and time-dependent manner. Oxymatrine also induced apoptosis and cell cycle arrest in the cells, in association with the upregulation of caspase-3 and Bax, and the downregulation of survivin, Bcl-2 and p53 expression. Overall, oxymatrine inhibits the proliferation of human bladder cancer cells by inducing apoptosis and cell cycle arrest via mechanisms that involve p53-Bax signaling and the downregulation of survivin expression. IntroductionBladder cancer is one of the most common malignant tumors of the urinary system worldwide, affecting 16.6 per 100,000 males and 3.6 per 100,000 females (1). Although surgery is the usual and effective way to treat bladder cancer, the 5-year recurrence rate is ~50% following surgical treatment (2,3). At present, intravesical chemotherapy is the most frequently used method to prevent the recurrence of bladder cancer, subsequent to surgery (4). However, chemotherapy is often associated with multidrug resistance and toxic side effects, with little specificity to cancer cells, which elucidates the challenges of applying chemotherapy to bladder cancers. Natural compounds have previously emerged as a potential treatment for cancer therapy; therefore, natural compounds may be a promising target for bladder cancer therapy.Matrine, the active compound that may be extracted from the Chinese herb Sophora flavecens, has previously been used to treat chronic hepatitis B, allergic dermatitis and hypoleukocytosis, in China (5,6). Matrine may transform into oxymatrine, which may also be extracted from Sophora flavecens, and the nitrogen-oxygen bond may split under certain conditions transforming oxymatrine back to matrine (7). Several studies have demonstrated the multiple beneficial effects of matrine, including anti-arrhythmia (8), anti-inflammation (9,10) and anti-fibrosis (11,12) effects, with minimal side effects reported. In addition, previous studies have shown that matrine induces apoptosis in several cancer cell lines, including breast cancer MCF-7 cells (13) and pancreatic cancer PANC1 cells (14), using various mechanisms, which potentiate the role of...

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Survivin beyond physiology: Orchestration of multistep carcinogenesis and therapeutic potentials

Cited by 58 publications

References 95 publications

AMPK/mTOR-mediated inhibition of survivin partly contributes to metformin-induced apoptosis in human gastric cancer cell

AMPK/mTOR-mediated inhibition of survivin partly contributes to metformin-induced apoptosis in human gastric cancer cell

CENP-H regulates the cell growth of human hepatocellular carcinoma cells through the mitochondrial apoptotic pathway

Oxymatrine inhibits proliferation of human bladder cancer T24 cells by inducing apoptosis and cell cycle arrest

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