Mucins and tumor resistance to chemotherapeutic drugs

Jonckheere, Nicolas; Skrypek, Nicolas; Seuningen, Isabelle Van

doi:10.1016/j.bbcan.2014.04.008

Cited by 76 publications

(78 citation statements)

References 137 publications

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“…It is a highly aggressive cancer that is usually diagnosed at an advanced stage and has the worst prognosis of any malignancy, with a 7% 5-year survival rate due to high chemoresistance. This chemoresistance is due in part to altered expressions of mucins, which form a mesh that makes target sites inaccessible to drugs (2)(3)(4)(5)(6)(7)(8)(9). Clinical and preclinical studies have shown aberrant expression of mucins during pancreatic cancer development.…”

Section: Introductionmentioning

confidence: 99%

“…The mucins may prevent drugs from accessing their sites of action. The expression of several mucins, including MUC1, MUC4, MUC5AC, and MUC16, is highly upregulated in pancreatic ductal adenocarcinoma (PDAC), pancreatic intraepithelial neoplasia (PanIN), intrapapillary mucinous neoplasms, and mucinous cystic neoplasms from patients with pancreatic cancer (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). The extent to which the dense mucin mesh influences the antiproliferative activity of 5-fluorouracil (5-FU) was investigated using human pancreatic cancer cells (2,3).…”

Section: Introductionmentioning

confidence: 99%

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Small-Molecule Inhibition of GCNT3 Disrupts Mucin Biosynthesis and Malignant Cellular Behaviors in Pancreatic Cancer

et al. 2016

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Pancreatic cancer is an aggressive neoplasm with almost uniform lethality and a 5-year survival rate of 7%. Several overexpressed mucins that impede drug delivery to pancreatic tumors have been therapeutically targeted, but enzymes involved in mucin biosynthesis have yet to be preclinically evaluated as potential targets. We used survival data from human patients with pancreatic cancer, next-generation sequencing of genetically engineered Kras-driven mouse pancreatic tumors and human pancreatic cancer cells to identify the novel core mucin-synthesizing enzyme GCNT3 (core 2 b-1,6 N-acetylglucosaminyltransferase). In mouse pancreatic cancer tumors, GCNT3 upregulation (103-fold; P < 0.0001) was correlated with increased expression of mucins (5 to 87-fold; P < 0.04-0.0003). Aberrant GCNT3 expression was also associated with increased mucin production, aggressive tumorigenesis, and reduced patient survival, and CRISPR-mediated knockout of GCNT3 in pancreatic cancer cells reduced proliferation and spheroid formation. Using in silico small molecular docking simulation approaches, we identified talniflumate as a novel inhibitor that selectively binds to GCNT3. In particular, docking predictions suggested that three notable hydrogen bonds between talniflumate and GCNT3 contribute to a docking affinity of À8.3 kcal/mol. Furthermore, talniflumate alone and in combination with low-dose gefitinib reduced GCNT3 expression, leading to the disrupted production of mucins in vivo and in vitro. Collectively, our findings suggest that targeting mucin biosynthesis through GCNT3 may improve drug responsiveness, warranting further development and investigation in preclinical models of pancreatic tumorigenesis.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Small-Molecule Inhibition of GCNT3 Disrupts Mucin Biosynthesis and Malignant Cellular Behaviors in Pancreatic Cancer

et al. 2016

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“…Cells were trypsinized, washed with complete medium and recovered in RPMI containing 2% FBS. Cells (5, 10 and 20x10 4 ) were allowed to attach for 2 h at 37˚C in a humidified 5% CO 2 incubator. Attached cells were first fixed with 1% glutaraldehyde for 10 min at room temperature and then stained with 0.1% crystal violet for 30 min at room temperature.…”

Section: Generation Of Muc5bsi and Mock Mcf-7 Cellsmentioning

confidence: 99%

“…There is a body of evidence indicating that mucins, not only constitute cancer biomarkers, but also play an active role in cancer progression by regulating cell growth, adhesion, invasion and signaling (2,3). Mucins are also involved in chemo-resistance to drugs (4). Thus, the implication of mucins and their associated carbohydrate antigens in the metastatic process of tumor cells makes them relevant targets for the prevention of metastasis and recurrence of cancers by immunotherapy in combination with effective chemotherapy (5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

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MUC5B silencing reduces chemo-resistance of MCF-7 breast tumor cells and impairs maturation of dendritic cells

García¹,

Tiscornia

Libisch

et al. 2016

International Journal of Oncology

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Abstract. Mucins participate in cancer progression by regulating cell growth, adhesion, signaling, apoptosis or chemo-resistance to drugs. The secreted mucin MUC5B, the major component of the respiratory tract mucus, is aberrantly expressed in breast cancer, where it could constitute a cancer biomarker. In this study we evaluated the role of MUC5B in breast cancer by gene silencing the MUC5B expression with short hairpin RNA on MCF-7 cells. We found that MUC5B-silenced MCF-7 cells have a reduced capacity to grow, adhere and form cell colonies. Interestingly, MUC5B knock-down increased the sensitivity to death induced by chemotherapeutic drugs. We also show that MUC5B silencing impaired LPS-maturation of DCs, and production of cytokines. Furthermore, MUC5B knock-down also influenced DC-differentiation and activation since it resulted in an upregulation of IL-1β, IL-6 and IL-10, cytokines that might be involved in cancer progression. Thus, MUC5B could enhance the production of LPS-induced cytokines, suggesting that the use of MUC5B-based cancer vaccines combined with DC-maturation stimuli, could favor the induction of an antitumor immune response.

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MUC13 overexpression in renal cell carcinoma plays a central role in tumor progression and drug resistance

Sheng

Lourie

et al. 2017

Int. J. Cancer

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Metastatic renal cell carcinoma is a largely incurable disease, and existing treatments targeting angiogenesis and tyrosine kinase receptors are only partially effective. Here we reveal that MUC13, a cell surface mucin glycoprotein, is aberrantly expressed by most renal cell carcinomas, with increasing expression positively correlating with tumor grade. Importantly, we demonstrated that high MUC13 expression was a statistically significant independent predictor of poor survival in two independent cohorts, particularly in stage 1 cancers. In cultured renal cell carcinoma cells MUC13 promoted proliferation and induced the cell cycle regulator, cyclin D1, and inhibited apoptosis by inducing the anti-apoptotic proteins, BCL-xL and survivin. Silencing of MUC13 expression inhibited migration and invasion, and sensitized renal cancer cells to killing by the multi-kinase inhibitors used clinically, sorafenib and sunitinib, and reversed acquired resistance to these drugs. Furthermore, we demonstrated that MUC13 promotion of renal cancer cell growth and survival is mediated by activation of nuclear factor κB, a transcription factor known to regulate the expression of genes that play key roles in the development and progression of cancer. These results show that MUC13 has potential as a prognostic marker for aggressive early stage renal cell cancer and is a plausible target to sensitize these tumors to therapy.

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Mucins and tumor resistance to chemotherapeutic drugs

Cited by 76 publications

References 137 publications

Small-Molecule Inhibition of GCNT3 Disrupts Mucin Biosynthesis and Malignant Cellular Behaviors in Pancreatic Cancer

Small-Molecule Inhibition of GCNT3 Disrupts Mucin Biosynthesis and Malignant Cellular Behaviors in Pancreatic Cancer

MUC5B silencing reduces chemo-resistance of MCF-7 breast tumor cells and impairs maturation of dendritic cells

MUC13 overexpression in renal cell carcinoma plays a central role in tumor progression and drug resistance

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