Persistent Activation of Stat3 Signaling Induces Survivin Gene Expression and Confers Resistance to Apoptosis in Human Breast Cancer Cells

Gritsko, Tanya; Williams, Amy; Turkson, James; Kaneko, Satoshi; Bowman, Tammy; Huang, Mei; Nam, Sangkil; Eweis, Ibrahim; Diaz, Nils M.; Sullivan, Daniel M.; Yoder, Sean; Enkemann, Steve; Eschrich, Steven; Lee, Ji‐Hyun; Beam, Craig A.; Cheng, Jin Q.; Minton, Susan; Muro-Cacho, Carlos; Jove, Richard

doi:10.1158/1078-0432.ccr-04-1752

Cited by 496 publications

(405 citation statements)

References 47 publications

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“…The response of cells to apoptotic stimuli depends on the balance between pro-and anti-apoptotic members of apoptosis family. The overexpression of both Bcl-X L and Bcl-2, survivin have been shown to prevent mitochondrial apoptosis in tumor cells [6,12]. Western blot analysis demonstrated that CDDOMe treatment results in the down regulation of these antiapoptotic proteins in paclitaxelresistant cells.…”

Section: Discussionmentioning

confidence: 99%

“…There is no therapy to overcome drug resistance in ovarian cancer. The development of chemoresistance is associated with many events, such as defective apoptotic signaling in response to drugs, overexpression of antiapoptotic proteins such interleukin 6 (IL-6), Bcl-2, BcL-X L , or survivin, and overexpression of multidrug resistance (MDR) gene protein pgp1 [6][7][8][9]12]. Successful management of ovarian cancer would be greatly aided by novel agents that interfere with both intrinsic and acquired mechanisms of drug resistance mechanisms.…”

Section: Introductionmentioning

confidence: 99%

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CDDO-Me, a synthetic triterpenoid, inhibits expression of IL-6 and Stat3 phosphorylation in multi-drug resistant ovarian cancer cells

Duan

Ames

Ryan

et al. 2008

Cancer Chemother Pharmacol

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Previous studies have identified interleukin 6 (IL-6) as an important cytokine with prognostic significance in ovarian cancer. Activation of the IL-6-Stat3 pathway contributes to tumor cell growth, survival and drug resistance in several cancers, including ovarian cancer. To explore potential therapeutic strategies for interrupting signaling through this pathway, we assessed the ability of CDDO-Me, a synthetic triterpenoid, to inhibit IL-6 secretion, Stat3 phosphorylation, Stat3 nuclear translocation and paclitaxel sensitivity in several cell line model systems. These studies demonstrated that CDDO-Me significantly inhibits IL-6 secretion in paclitaxel-resistant ovarian cancer cells and specifically suppresses IL-6-or oncostatin M-induced Stat3 nuclear translocation. Treatment with CDDO-Me significantly decreases the levels of Stat3, Jak2, and Src phosphorylation in ovarian and breast cancer cell lines with constitutively activated Stat3. This inhibition of the IL-6-Stat3 pathway correlated with suppression of the anti-apoptotic Stat3 target genes Bcl-X L , survivin, and Mcl-1, and with apoptosis induction as measured by monitoring PARP and its cleavage product, as well as by quantitative measurement of the apoptosis-associated CK18Asp396. Furthermore, CDDO-Me increases the cytotoxic effects of paclitaxel in the paclitaxel-resistant ovarian cancer cell line OVCAR8 TR (2 to 5 fold) and of cisplatin in the cisplatin-resistant ovarian cancer cell line A2780cp70 (2 to 4 fold). Our data confirm that CDDO-Me interrupts the signaling of multiple kinases involved in the IL-6-Stat3 and Src signaling pathways. Inhibition is likely achieved through multiple points within these pathways. In a model system of established acquired drug resistance, CCDO-Me is effective at partially reversing the drug-resistance phenotype.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CDDO-Me, a synthetic triterpenoid, inhibits expression of IL-6 and Stat3 phosphorylation in multi-drug resistant ovarian cancer cells

Duan

Ames

Ryan

et al. 2008

Cancer Chemother Pharmacol

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“…24 The relationship between survivin and STAT3 is somewhat more complicated than that between survivin and p53. STAT3 directly binds to and regulates the survivin promoter, 63 and STAT3 activation induces survivin expression and rescues cells from apoptosis. 25,63 However, survivin can also bind to STAT3 dimers and repress STAT3 transactivation of target gene promoters.…”

Section: Discussionmentioning

confidence: 99%

“…STAT3 directly binds to and regulates the survivin promoter, 63 and STAT3 activation induces survivin expression and rescues cells from apoptosis. 25,63 However, survivin can also bind to STAT3 dimers and repress STAT3 transactivation of target gene promoters. 64 Thus, clarifying the mechanism underlying the association of STAT3-survivin coexpression with better overall survival and progression-free survival is difficult.…”

Section: Discussionmentioning

confidence: 99%

Prognostic and biological significance of survivin expression in patients with diffuse large B-cell lymphoma treated with rituximab-CHOP therapy

et al. 2015

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Survivin, a member of the inhibitor of apoptosis protein family, is overexpressed in a variety of human neoplasms. The prognostic significance of survivin expression in diffuse large B-cell lymphoma patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is unclear. We used standard immunohistochemistry methods to quantify survivin expression in 463 patients with de novo diffuse large B-cell lymphoma who received the R-CHOP. Of the 463 patients, 269 (58%) had survivin overexpression with a cutoff of 425%, associated with an International Prognostic Index score of 42 (P = 0.015), disease in ≥ 2 extranodal sites (P = 0.011), and a high Ki-67 index (Po 0.0001). Among patients with activated B cell-like disease, the overall survival rate of survivin-positive patients was significantly lower than that of survivinnegative patients (P = 0.033); multivariate analysis confirmed that in these patients, survivin overexpression was an independent prognostic factor for survival. Among patients with wild-type p53 overexpression, the overall survival and progression-free survival rates of the survivin-positive group were significantly lower than those of the survivin-negative group (P = 0.035 and P = 0.04 respectively). In STAT3-positive patients, survivin overexpression was associated with significantly better survival. Among patients with activated B cell-like disease, survivin-positive compared with survivin-negative groups had significantly different gene expression signatures, including genes involved in mitosis or tumor cell proliferation. Our results indicate that survivin is an

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“…3C). Since expression of cyclin D1, Bcl-xL and Survivin required positive transcriptional control of STAT3 [30,31], the observed changes in these levels were expected. In contrast, levels of anti-apoptotic protein XIAP did not notably decrease after RSV treatment in LU1205.…”

Section: Signaling Pathways Affected By Rsv In Lu1205 Melanoma Cellsmentioning

confidence: 92%

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

Ivanov

Partridge

Johnson

et al. 2008

Experimental Cell Research

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Although many human melanomas express the death receptors TRAIL-R2/DR5 or TRAIL-R1/ DR4 on cell surface, they often exhibit resistance to exogenous TRAIL. One of the main contributors to TRAIL-resistance of melanoma cells is upregulation of transcription factors STAT3 and NF-κB that control the expression of antiapoptotic genes, including cFLIP and BclxL. On the other hand, the JNK-cJun pathway is involved in the negative regulation of cFLIP (a caspase-8 inhibitor) expression. Our observations indicated that resveratrol, a polyphenolic phytoalexin, decreased STAT3 and NF-κB activation, while activating JNK-cJun that finally suppressed expression of cFLIP and Bcl-xL proteins and increased sensitivity to exogenous TRAIL in DR5-positive melanomas. Interestingly, resveratrol did not increase surface expression of DR5 in human melanomas, while γ-irradiation or sodium arsenite treatment substantially upregulated DR5 expression. Hence, an initial increase in DR5 surface expression (either by γ-irradiation or arsenite), and subsequent downregulation of antiapoptotic cFLIP and Bcl-xL (by resveratrol), appear to constitute an efficient approach to reactivate apoptotic death pathways in TRAIL-resistant human melanomas. In spite of partial suppression of mitochondrial function and the mitochondrial death pathway, melanoma cells still retain the potential to undergo the DR5-mediated, caspase-8-dependent death pathway that could be accelerated by either an increase in DR5 surface expression or suppression of cFLIP. Taken together, these results suggest that resveratrol, in combination with TRAIL, may have a significant efficacy in the treatment of human melanomas.

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Persistent Activation of Stat3 Signaling Induces Survivin Gene Expression and Confers Resistance to Apoptosis in Human Breast Cancer Cells

Cited by 496 publications

References 47 publications

CDDO-Me, a synthetic triterpenoid, inhibits expression of IL-6 and Stat3 phosphorylation in multi-drug resistant ovarian cancer cells

CDDO-Me, a synthetic triterpenoid, inhibits expression of IL-6 and Stat3 phosphorylation in multi-drug resistant ovarian cancer cells

Prognostic and biological significance of survivin expression in patients with diffuse large B-cell lymphoma treated with rituximab-CHOP therapy

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

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