Survivin’s Dual Role: An Export’s View

Knauer, Shirley K.; Mann, Wolf J.; Stauber, Roland H.

doi:10.4161/cc.6.5.3902

Cited by 66 publications

(60 citation statements)

References 23 publications

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“…Cytoplasmic survivin predominantly mediates the antiapoptotic function, whereas nuclear survivin mediates the mitotic function and is significantly less stable (32,48). Cytoplasmic survivin has been shown to be particularly high in rectal tumors and to be an independent predictor of poor prognosis, whereas nuclear survivin has been a favorable factor (38,49,50).…”

Section: Discussionmentioning

confidence: 99%

“…XPO1 plays an essential role in the function of survivin, as its cytoplasmic localization is required for antiapoptotic and tumor-promoting functions of survivin (27,28). Studies using mutants with export-deficient survivin showed that tumor cells were more sensitive to radiotherapy-induced apoptosis (28,31,32). On the basis of these studies, we hypothesize that blocking survivin nuclear export using XPO1 inhibitors could prevent radiation resistance.…”

Section: Introductionmentioning

confidence: 97%

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XPO1 Inhibition Enhances Radiation Response in Preclinical Models of Rectal Cancer

Ferreiro-Neira

Torres

Liesenfeld

et al. 2016

Clinical Cancer Research

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Purpose: Combination of radiation with radiosensitizing chemotherapeutic agents improves outcomes for locally advanced rectal cancer. Current treatment includes 5-fluorouracil-based chemoradiation prior to surgical resection; however pathologic complete response varies from 15% to 20%, prompting the need to identify new radiosensitizers. Exportin 1 (XPO1, also known as chromosome region 1, CRM1) mediates the nuclear export of critical proteins required for rectal cancer proliferation and treatment resistance. We hypothesize that inhibition of XPO1 may radiosensitize cancer cells by altering the function of these critical proteins resulting in decreased radiation resistance and enhanced antitumoral effects.Experimental Design: To test our hypothesis, we used the selective XPO1 inhibitor, selinexor, to inhibit nuclear export in combination with radiation fractions similar to that given in clinical practice for rectal cancer: hypofractionated short-course radiation dosage of 5 Gy per fraction or the conventional longcourse radiation dosage of 1 Gy fractions. Single and combination treatments were tested in colorectal cancer cell lines and xenograft tumor models.Results: Combination treatment of radiotherapy and selinexor resulted in an increase of apoptosis and decrease of proliferation compared with single treatment, which correlated with reduced tumor size. We found that the combination promoted nuclear survivin accumulation and subsequent depletion, resulting in increased apoptosis and enhanced radiation antitumoral effects.Conclusions: Our findings suggest a novel therapeutic option for improving radiation sensitivity in the setting of rectal cancer and provide the scientific rationale to evaluate this combination strategy for clinical trials.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

XPO1 Inhibition Enhances Radiation Response in Preclinical Models of Rectal Cancer

Ferreiro-Neira

Torres

Liesenfeld

et al. 2016

Clinical Cancer Research

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“…25 Presence of this complex at the right place at the right time is the key to precise control of Aurora B kinase. [26][27][28] Regulation of the protein amounts of Aurora B determines the timing of Aurora B activity.…”

Section: Discussionmentioning

confidence: 99%

FBXW7 is involved in Aurora B degradation

et al. 2012

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“…The sequences in zebrafish sur1 (LKKTVDSLTV) and sur2 (MSKTFDELTA) were also very similar to a known nuclear export signal in human survivin (VKKQFEELTL) that is necessary for the cytoplasmic localization of the proteins. 16 Phylogenetic analysis (Figure 1b) of vertebrate survivins showed that zebrafish sur1 and human sur were distinct from zebrafish sur2, suggesting that the duplication of this gene occurred in the common ancestors of teleosts and tetrapods. As a major genome duplication has occurred in the teleost lineage after its divergence from the tetrapods, 17 additional survivin duplicate may occur in the zebrafish genome.…”

Section: Sur1 and Sur2 Are Highly Conserved Over The Bir Domainmentioning

confidence: 99%