Survivin and pancreatic cancer

Liu, Binbin; Wang, Weihong

doi:10.5306/wjco.v2.i3.164

Cited by 30 publications

(25 citation statements)

References 28 publications

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“…Survivin is a member of the 'inhibitor of apoptosis' (IAP) gene family of proteins that is barely detected in normal tissues (35,36). However, survivin appears to be selectively expressed in transformed cells and in most human cancers, including pancreatic carcinomas (31,37). It has been previously reported that inhibition of Stat3 signaling blocked the expression of survivin protein and induced apoptosis in breast cancer cells (38).…”

Section: Discussionmentioning

confidence: 99%

Pim-3 promotes human pancreatic cancer growth by regulating tumor vasculogenesis

Liu

Wang

Li³

et al. 2014

Oncology Reports

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Copyright: Zhang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Ovarian cancer-associated antigen 12 (OVA12) was first identified in an ovarian carcinoma complementary DNA (cDNA) expression library and has been shown to play an important role in tumor growth. Here, we found that overexpression of OVA12 accelerated tumor growth in different tumor cells, whereas OVA12 depletion was associated with the opposite effect. Moreover, knocking down OVA12 led to a significant increase in the protein levels of p53, and the overexpression of OVA12 significantly decreased endogenous p53 levels. In addition, OVA12 stimulated p53 polyubiquitination and degradation by the proteasome and promoted tumor growth at least partially through the p53 pathway. Taken together, these results indicate that OVA12 is a negative regulator of p53 and that inhibition of OVA12 expression might serve as a therapeutic target to restore tumor suppression.

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Section: Discussionmentioning

confidence: 99%

Pim-3 promotes human pancreatic cancer growth by regulating tumor vasculogenesis

Liu

Wang

Li³

et al. 2014

Oncology Reports

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“…Survivin is a member of the inhibitors of apoptosis protein family and is overexpressed in most common human cancers including breast, prostate, pancreatic, and hematological malignancies (16)(17)(18)(19)(20)(21). It plays a vital role in oncogenesis by being involved in both cell cycle control and resistance to apoptosis (22).…”

Section: Introductionmentioning

confidence: 99%

Selinexor (KPT-330) Induces Tumor Suppression through Nuclear Sequestration of IκB and Downregulation of Survivin

Nair

Musi

Schwartz

2017

Clinical Cancer Research

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Purpose: Selinexor, a small molecule that inhibits nuclear export protein XPO1, has demonstrated efficacy in solid tumors and hematologic malignancies with the evidence of clinical activity in sarcoma as a single agent. Treatment options available are very few, and hence the need to identify novel targets and strategic therapies is of utmost importance.Experimental Design: The mechanistic effects of selinexor in sarcomas as a monotherapy and in combination with proteasome inhibitor, carfilzomib, across a panel of cell lines in vitro and few in xenograft mouse models were investigated.Results: Selinexor induced IkB nuclear localization as a single agent, and the effect was enhanced by stabilization of IkB when pretreated with the proteasome inhibitor carfilzomib. This stabilization and retention of IkB in the nucleus resulted in inhibition of NFkB and transcriptional suppression of the critical antiapoptotic protein, survivin. Treatment of carfilzomib followed by selinexor caused selinexor-sensitive and selinexor-resistant cell lines to be more sensitive to selinexor as determined by an increase in apoptosis. This was successfully demonstrated in the MPNST xenograft model with enhanced tumor suppression.Conclusions: The subcellular distributions of IkB and NFkB are indicative of carcinogenesis. Inhibition of XPO1 results in intranuclear retention of IkB, which inhibits NFkB and thereby provides a novel mechanism for drug therapy in sarcoma. This effect can be further enhanced in relatively selinexor-resistant sarcoma cell lines by pretreatment with the proteasome inhibitor carfilzomib. Because of these results, a human clinical trial with selinexor in combination with a proteasome inhibitor is planned for the treatment of sarcoma.

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“…S2B). We then evaluated if PA affected the levels of survivin, an anti-apoptotic protein highly expressed in PC (28). Treatment of Panc-1 cells with PA reduced survivin levels in a time-dependent manner (Fig.…”

Section: Resultsmentioning

confidence: 99%

Phospho-Aspirin (MDC-22) Prevents Pancreatic Carcinogenesis in Mice

Mattheolabakis

Papayannis

Yang

et al. 2016

Cancer Prevention Research

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Pancreatic cancer (PC) is a deadly disease with a dismal 5-year survival rate of <6%. The currently limited treatment options for PC underscore the need for novel chemopreventive and therapeutic agents. Accumulating evidence indicates that aspirin use is associated with a decreased risk of PC. However, the anticancer properties of aspirin are restricted by its gastrointestinal toxicity and its limited efficacy. Therefore, we developed phospho-aspirin (PA; MDC-22), a novel derivative of aspirin, and evaluated its chemopreventive efficacy in preclinical models of PC. PA inhibited the growth of human PC cell lines 8–12 fold more potently than aspirin; based on the 24-h IC50 values. In a Panc-1 xenograft model, PA, at a dose of 100 mg/kg/d ×5/wk for 30 days, reduced tumor growth by 78% (p<0.01 vs vehicle control). Furthermore, PA prevented pancreatitis-accelerated acinar-to-ductal metaplasia in mice with activated Kras. In p48-Cre;KrasG12D mice, cerulein treatment (6 hourly injections 2×/wk × 3 wks) led to a significant increase in ductal metaplasia, replacing the majority of the exocrine compartment. Administration of PA 100 mg/kg/d ×5/wk for 21 days (starting on the first day of cerulein injection) inhibited the acinar-to-ductal metaplasia, reducing it by 87% (p<0.01, vs cerulein-treated control). PA appeared to be safe, with the animals showing no signs of toxicity during treatment. Mechanistically, PA inhibited EGFR activation in PC, an effect consistently observed in PC cells, primary acinar explants and in vivo. In conclusion, our findings indicate that PA has strong anticancer efficacy in preclinical models of PC, warranting its further evaluation.

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Survivin and pancreatic cancer

Cited by 30 publications

References 28 publications

Pim-3 promotes human pancreatic cancer growth by regulating tumor vasculogenesis

Pim-3 promotes human pancreatic cancer growth by regulating tumor vasculogenesis

Selinexor (KPT-330) Induces Tumor Suppression through Nuclear Sequestration of IκB and Downregulation of Survivin

Phospho-Aspirin (MDC-22) Prevents Pancreatic Carcinogenesis in Mice

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