The oncogenic phosphatase PPM1D confers cisplatin resistance in ovarian carcinoma cells by attenuating checkpoint kinase 1 and p53 activation

Alayoud, Ahmed; Abedini, Mohammad Reza; Tsang, Benjamin K.

doi:10.1038/onc.2011.399

Cited by 66 publications

(62 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1H) (16); and multidrug resistant OVCAR-3 ovarian cancer cells, which are resistant to 5 μM ICI (Fig. 1I) and to paclitaxel, cisplatin, and other anticancer drugs (17,18). BHPI blocked proliferation in all 15 ERα + cell lines and at 10 μM had no effect on proliferation in all 12 ERα − cell lines tested (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 99%

Estrogen receptor α inhibitor activates the unfolded protein response, blocks protein synthesis, and induces tumor regression

Andruska¹,

Zheng²,

Yang³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

140

View full text Add to dashboard Cite

Recurrent estrogen receptor α (ERα)-positive breast and ovarian cancers are often therapy resistant. Using screening and functional validation, we identified BHPI, a potent noncompetitive small molecule ERα biomodulator that selectively blocks proliferation of drug-resistant ERα-positive breast and ovarian cancer cells. In a mouse xenograft model of breast cancer, BHPI induced rapid and substantial tumor regression. Whereas BHPI potently inhibits nuclear estrogen-ERα-regulated gene expression, BHPI is effective because it elicits sustained ERα-dependent activation of the endoplasmic reticulum (EnR) stress sensor, the unfolded protein response (UPR), and persistent inhibition of protein synthesis. BHPI distorts a newly described action of estrogen-ERα: mild and transient UPR activation. In contrast, BHPI elicits massive and sustained UPR activation, converting the UPR from protective to toxic. In ERα + cancer cells, BHPI rapidly hyperactivates plasma membrane PLCγ, generating inositol 1,4,5-triphosphate (IP 3 ), which opens EnR IP 3 R calcium channels, rapidly depleting EnR Ca 2+ stores. This leads to activation of all three arms of the UPR. Activation of the PERK arm stimulates phosphorylation of eukaryotic initiation factor 2α (eIF2α), resulting in rapid inhibition of protein synthesis. The cell attempts to restore EnR Ca 2+ levels, but the open EnR IP 3 R calcium channel leads to an ATP-depleting futile cycle, resulting in activation of the energy sensor AMP-activated protein kinase and phosphorylation of eukaryotic elongation factor 2 (eEF2). eEF2 phosphorylation inhibits protein synthesis at a second site. BHPI's novel mode of action, high potency, and effectiveness in therapyresistant tumor cells make it an exceptional candidate for further mechanistic and therapeutic exploration.estrogen receptor | drug discovery | breast cancer | unfolded protein response | ovarian cancer E strogens, acting via estrogen receptor α (ERα), stimulate tumor growth (1-3). Approximately 70% of breast cancers are ERα-positive and most deaths due to breast cancer are in patients with ERα + tumors (2, 4). Endocrine therapy using aromatase inhibitors to block estrogen production, or tamoxifen and other competitor antiestrogens, often results in selection and outgrowth of resistant tumors. Although 30-70% of epithelial ovarian tumors are ERα-positive (1), endocrine therapy is largely ineffective (5-7). After several cycles of chemotherapy, tumors recur as resistant ovarian cancer (5), and most patients die within 5 years (8).Noncompetitive ERα inhibitors targeting this unmet therapeutic need, including DIBA, TPBM, TPSF, and LRH-1 inhibitors that reduce ERα levels, show limited specificity, require high concentrations (>5 μM), and usually have not advanced through preclinical development (9-12). These noncompetitive ERα inhibitors and competitor antiestrogens are primarily cytostatic and act by preventing estrogen-ERα action; therefore, they are largely ineffective in therapy-resistant ERα containing cancer cells that no longer requi...

show abstract

Section: Resultsmentioning

confidence: 99%

Estrogen receptor α inhibitor activates the unfolded protein response, blocks protein synthesis, and induces tumor regression

Andruska¹,

Zheng²,

Yang³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

140

View full text Add to dashboard Cite

show abstract

“…Absorbance at 490 nm was determined by a Bio-Rad X-Mark microplate analyzer. Apoptosis was assessed based on stereotypic morphological changes, including chromatin condensation, nuclear fragmentation cytoplasmic shrinkage, and the formation of apoptotic bodies (with nuclear fragments) as assessed in previous studies (11,27,28). At least 400 cells/treatment group were counted, and the quantification process was blinded to avoid experiment bias.…”

Section: Mts Assay and Hoechst 33258mentioning

confidence: 99%

Piceatannol Enhances Cisplatin Sensitivity in Ovarian Cancer via Modulation of p53, X-linked Inhibitor of Apoptosis Protein (XIAP), and Mitochondrial Fission

Farrand

Byun

Kim

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Chemotherapeutic sensitivity in ovarian cancer is dependent on effective apoptosis signaling. Results: Piceatannol enhances cisplatin sensitivity by modulating p53, XIAP (X-linked inhibitor of apoptosis protein), and mitochondrial fission in vitro and in vivo. Conclusion: Piceatannol is a potent enhancer of cisplatin-induced apoptosis. Significance: Piceatannol exhibits potential for clinical development for the treatment of ovarian cancer.

show abstract

“…To test this hypothesis, we utilized a series of biophysical and biochemical techniques to understand the response of ovarian cancer cells to a soft matrix similar to adipose tissue and a stiff matrix similar to tumor tissue (Samani et al, 2007;Tse and Engler, 2010), using both the more-metastatic SKOV-3 and the lessmetastatic OVCAR-3 human cell lines (Slack-Davis et al, 2009), both of which harbor either mutated or deleted p53, indicative of high-grade serous ovarian carcinomas (Ali et al, 2012;Domcke et al, 2013;Salani et al, 2008). We found that OCCs show increased adhesion on soft microenvironments.…”

Section: Introductionmentioning

confidence: 99%

Metastatic ovarian cancer cell malignancy is increased on soft matrices through a mechanosensitive Rho/ROCK pathway

McGrail

Kieu

Dawson

2014

Journal of Cell Science

102

View full text Add to dashboard Cite

Although current treatments for localized ovarian cancer are highly effective, this cancer still remains the most lethal gynecological malignancy, largely owing to the fact that it is often detected only after tumor cells leave the primary tumor. Clinicians have long noted a clear predilection for ovarian cancer to metastasize to the soft omentum. Here, we show that this tropism is due not only to chemical signals but also mechanical cues. Metastatic ovarian cancer cells (OCCs) preferentially adhere to soft microenvironments and display an enhanced malignant phenotype, including increased migration, proliferation and chemoresistance. To understand the cell-matrix interactions that are used to sense the substrate rigidity, we utilized traction force microscopy (TFM) and found that, on soft substrates, human OCCs increased both the magnitude of traction forces as well as their degree of polarization. After culture on soft substrates, cells underwent morphological elongation characteristic of epithelial-to-mesenchymal transition (EMT), which was confirmed by molecular analysis. Consistent with the idea that mechanical cues are a key determinant in the spread of ovarian cancer, the observed mechanosensitivity was greatly decreased in lessmetastatic OCCs. Finally, we demonstrate that this mechanical tropism is governed through a Rho-ROCK signaling pathway.

show abstract

The oncogenic phosphatase PPM1D confers cisplatin resistance in ovarian carcinoma cells by attenuating checkpoint kinase 1 and p53 activation

Cited by 66 publications

References 45 publications

Estrogen receptor α inhibitor activates the unfolded protein response, blocks protein synthesis, and induces tumor regression

Estrogen receptor α inhibitor activates the unfolded protein response, blocks protein synthesis, and induces tumor regression

Piceatannol Enhances Cisplatin Sensitivity in Ovarian Cancer via Modulation of p53, X-linked Inhibitor of Apoptosis Protein (XIAP), and Mitochondrial Fission

Metastatic ovarian cancer cell malignancy is increased on soft matrices through a mechanosensitive Rho/ROCK pathway

Contact Info

Product

Resources

About