The Role of HuR in Gemcitabine Efficacy in Pancreatic Cancer: HuR Up-regulates the Expression of the Gemcitabine Metabolizing Enzyme Deoxycytidine Kinase

Costantino, Christina L.; Witkiewicz, Agnieszka K.; Kuwano, Yuki; Cozzitorto, Joseph A.; Kennedy, Eugene P.; Dasgupta, Abhijit; Keen, Judith C.; Yeo, Charles J.; Gorospe, Myriam; Brody, Jonathan R.

doi:10.1158/0008-5472.can-09-0371

Cited by 158 publications

(253 citation statements)

References 16 publications

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“…Increased expression levels of HuR may increase the cytotoxicity of GEM and reduce chemoresistance to this drug in a variety of malignant cell types. A previous in vitro study demonstrated that the modulation of dCK expression via HuR overexpression markedly sensitized pancreatic cancer cells to GEM (11). Similar results were identified in human gallbladder cancer cells (14), and an in vivo study has also demonstrated that the status of HuR expression in various cancer cells is closely associated with response to GEM and GEM-based chemotherapy in patients with pancreatic cancer (11,15).…”

Section: Introductionsupporting

confidence: 63%

“…numerous types of malignancy have been investigated in vivo and in vitro (5)(6)(7)(8)(9)(10)28). To the best of our knowledge, the first study that identified upregulated HuR expression as a significant marker for an improved response to GEM-based chemotherapy in patients with pancreatic cancer was published in 2009 (11). The study also observed that high HuR expression levels predicted a favorable prognosis in these patients (11).…”

Section: Discussionmentioning

confidence: 99%

“…HuR expression was evaluated based on an immunoreactive staining score, as previously reported (8,11). HuR expression was evaluated separately in cancer cell cytoplasm and nuclei.…”

Section: Patientsmentioning

confidence: 99%

“…Another important function of HuR is to increase the protein expression of deoxycytidine kinase (dCK), a key enzyme involved in metabolizing the prodrug GEM into its active metabolites through phosphorylation (11). Consequently, increased expression levels of dCK may be associated with certain anticancer effects of GEM.…”

Section: Introductionmentioning

confidence: 99%

“…A previous in vitro study demonstrated that the modulation of dCK expression via HuR overexpression markedly sensitized pancreatic cancer cells to GEM (11). Similar results were identified in human gallbladder cancer cells (14), and an in vivo study has also demonstrated that the status of HuR expression in various cancer cells is closely associated with response to GEM and GEM-based chemotherapy in patients with pancreatic cancer (11,15). Thus, HuR may have an important role in the GEM-based chemotherapy of patients with cancer (16).…”

Section: Introductionmentioning

confidence: 99%

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Human antigen R as a predictive marker for response to gemcitabine-based chemotherapy in advanced cisplatin-resistant urothelial cancer

et al. 2016

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Abstract. In patients with advanced urothelial cancer (UC), a combination of cisplatin (CDDP) and gemcitabine (GEM) is the most commonly used first-line systematic chemotherapy regimen. Although no standard regime for the treatment of CDDP-resistant UC has been established, GEM-based regimens are frequently used in these patients. In other types of cancer, human antigen R (HuR) status in cancer cells is closely associated with patient response to GEM. The aim of the present study was to establish the predictive potential of HuR expression for disease progression and survival in patients with UC who were treated with GEM-based regimens as a first or second-line chemotherapy. A total of 50 patients with advanced UC were enrolled in the current study. As first-line chemotherapy, methotrexate, vinblastine, epirubicin and CDDP (MVEC) combination therapy and GEM and CDDP combination therapy were administered in 34 (68.0%) and 16 patients (32.0%), respectively. Following progression, 45 patients (90.0%) were treated with combined GEM and paclitaxel therapy, and 5 patients (10.0%) were treated with GEM monotherapy. Cytoplasmic and nuclear HuR expression was evaluated using immunohistochemical techniques. The associations between HuR expression levels and local tumor response and treatment outcomes were analyzed. In first-line chemotherapy, no anticancer effects were observed to be significantly associated with nuclear or cytoplasmic HuR expression. In second-line chemotherapy nuclear HuR expression also exhibited no significant association with anticancer effects; however, the local tumor response was significantly improved if positive cytoplasmic HuR expression was present (P=0.002). Multivariate analyses revealed that cytoplasmic HuR expression levels were a significant predictive marker for longer OS (hazard ratio, 0.22; 95% confidence interval, 0.09-0.56; P=0.001). No significant association was observed between nuclear HuR expression levels and the overall survival. Therefore, cytoplasmic HuR expression is a significant predictive marker of response to GEM-based chemotherapy in patients with CDDP-resistant UC. Despite the limitations of a small and retrospective study, the results of the present study may facilitate the development of novel treatment strategies and provide a focus for additional basic and clinical studies.

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Section: Introductionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

“…HuR expression was evaluated based on an immunoreactive staining score, as previously reported (8,11). HuR expression was evaluated separately in cancer cell cytoplasm and nuclei.…”

Section: Patientsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Human antigen R as a predictive marker for response to gemcitabine-based chemotherapy in advanced cisplatin-resistant urothelial cancer

et al. 2016

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Suramin, screened from an approved drug library, inhibits HuR functions and attenuates malignant phenotype of oral cancer cells

et al. 2018

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AU‐rich elements (ARE) exist in the 3′‐untranslated regions of the mRNA transcribed from cell growth‐related genes such as proto‐oncogenes, cyclin‐related genes, and growth factors. HuR binds and stabilizes ARE‐mRNA. HuR is expressed abundantly in cancer cells and related malignant phenotypes. HuR knockdown attenuates the malignant phenotype of oral cancer cells. In this study, we screened 1570 compounds in the approved drug library by differential scanning fluorimetry (DSF) to discover a HuR‐targeted compound. Firstly, 55 compounds were selected by DSF. Then, 8 compounds that showed a shift in the melting temperature value in a concentration‐dependent manner were selected by DSF. Of them, suramin, an anti‐trypanosomal drug, binds to HuR, exhibiting fast‐on and fast‐off kinetic behavior on surface plasmon resonance (SPR). We confirmed that suramin significantly decreased mRNA and protein expression of cyclin A2 and cyclin B1. The cyclin A2 and cyclin B1 mRNAs were destabilized by suramin. Furthermore, the motile and invasive activities of a tongue carcinoma cell line treated with suramin were markedly lower than those of control cells. The above findings suggest that suramin binds to HuR and inhibits its function. We also showed that the anticancer effects of suramin were caused by the inhibition of HuR function, indicating its potential as a novel therapeutic agent in the treatment of oral cancer. Our results suggest that suramin, via its different mechanism, may effectively suppress progressive oral cancer that cannot be controlled using other anticancer agents.

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The new standard of HCV therapy: Retreatment in experienced patients†,‡

Gara

Ghany

2012

Clinical Liver Disease

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The Role of HuR in Gemcitabine Efficacy in Pancreatic Cancer: HuR Up-regulates the Expression of the Gemcitabine Metabolizing Enzyme Deoxycytidine Kinase

Abstract: RNA-binding protein

Cited by 158 publications

References 16 publications

Human antigen R as a predictive marker for response to gemcitabine-based chemotherapy in advanced cisplatin-resistant urothelial cancer

Human antigen R as a predictive marker for response to gemcitabine-based chemotherapy in advanced cisplatin-resistant urothelial cancer

Suramin, screened from an approved drug library, inhibits HuR functions and attenuates malignant phenotype of oral cancer cells

The new standard of HCV therapy: Retreatment in experienced patients†,‡

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