MUC1 induces drug resistance in pancreatic cancer cells via upregulation of multidrug resistance genes

Nath, Sritama; Daneshvar, K.; Roy, Lopamudra Das; Grover, Priyanka; Kidiyoor, Amritha; Mosley, LaSharon Denise; Sahraei, Mahnaz; Mukherjee, Pinku

doi:10.1038/oncsis.2013.16

Cited by 139 publications

(157 citation statements)

References 28 publications

Supporting

Mentioning

152

Contrasting

Order By: Relevance

“…The expression of ATP-binding cassette transporters, which act as drug efflux pumps, is also associated with drug resistance in PDAC (36). The drug efflux pumps ABCB1 (MDR1/P-glycoprotein) and ABCC1 (MRP1) have been linked to the resistance of PDAC cells to gemcitabine (37,38). CYR61 has been previously reported to regulate expression of the drug efflux pump MDR1/P-glycoprotein in renal cell carcinoma (39), but it has not been studied in PDAC.…”

Section: Cyr61 Does Not Regulate Expression Of Other Gemcitabine Resimentioning

confidence: 99%

TGF-β-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3

Hesler¹,

Huang²,

Starr³

et al. 2016

CARCIN

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer in part due to inherent resistance to chemotherapy, including the first-line drug gemcitabine. Although low expression of the nucleoside transporters hENT1 and hCNT3 that mediate cellular uptake of gemcitabine has been linked to gemcitabine resistance, the mechanisms regulating their expression in the PDAC tumor microenvironment are largely unknown. Here, we report that the matricellular protein cysteine-rich angiogenic inducer 61 (CYR61) negatively regulates the nucleoside transporters hENT1 and hCNT3. CRISPR/Cas9-mediated knockout of CYR61 increased expression of hENT1 and hCNT3, increased cellular uptake of gemcitabine and sensitized PDAC cells to gemcitabine-induced apoptosis. In PDAC patient samples, expression of hENT1 and hCNT3 negatively correlates with expression of CYR61. We demonstrate that stromal pancreatic stellate cells (PSCs) are a source of CYR61 within the PDAC tumor microenvironment. Transforming growth factor-β (TGF-β) induces the expression of CYR61 in PSCs through canonical TGF-β-ALK5-Smad2/3 signaling. Activation of TGF-β signaling or expression of CYR61 in PSCs promotes resistance to gemcitabine in PDAC cells in an in vitro co-culture assay. Our results identify CYR61 as a TGF-β-induced stromal-derived factor that regulates gemcitabine sensitivity in PDAC and suggest that targeting CYR61 may improve chemotherapy response in PDAC patients.

show abstract

Section: Cyr61 Does Not Regulate Expression Of Other Gemcitabine Resimentioning

confidence: 99%

TGF-β-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3

Hesler¹,

Huang²,

Starr³

et al. 2016

CARCIN

View full text Add to dashboard Cite

show abstract

“…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%

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

et al. 2016

View full text Add to dashboard Cite

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.

show abstract

“…Mucin 1 protein has been implicated in various aspects of tumor development, including angiogenesis (7), proliferation (8), migration (9), survival (10) and metastasis (11). Accumulating evidence indicates a causal association between MUC1 expression and chemoresistance of tumor cells (12,13). For instance, Nath et al (12) reported that MUC1 contributes to drug resistance in pancreatic cancer cells through upregulation of multidrug resistance genes, including ATP binding cassette subfamily C member (ABCC)1, ABCC3, ABCC5 and ABCB1.…”

Section: Introductionmentioning

confidence: 99%

“…Accumulating evidence indicates a causal association between MUC1 expression and chemoresistance of tumor cells (12,13). For instance, Nath et al (12) reported that MUC1 contributes to drug resistance in pancreatic cancer cells through upregulation of multidrug resistance genes, including ATP binding cassette subfamily C member (ABCC)1, ABCC3, ABCC5 and ABCB1. Overexpression of the oncogenic MUC1-C subunit has been identified to confer tamoxifen resistance in MCF-7 breast cancer cells (13).…”

Section: Introductionmentioning

confidence: 99%

Mucin 1 promotes radioresistance in hepatocellular carcinoma cells through activation of JAK2/STAT3 signaling

2017

Oncol Lett

View full text Add to dashboard Cite

Abstract. Mucin 1 (MUC1) is aberrantly overexpressed in numerous human cancer types, including hepatocellular carcinoma (HCC) and contributes to chemoresistance of tumor cells. The aim of the present study was to evaluate the possible implication of MUC1 in radioresistance of HCC cells and the underlying mechanisms. It was demonstrated that MUC1 was significantly upregulated in HCC cells following irradiation exposure, which was coupled with increased phosphorylation of signal transducer and activator of transcription 3 (STAT3). Enforced expression of MUC1 significantly (P<0.05) promoted the clonogenic survival of HCC cells following irradiation compared with empty vector-transfected cells. MUC1 overexpression resulted in >60% reduction in apoptosis induced by irradiation, as determined by Annexin-V/propidium iodide double staining and flow cytometry analysis. Furthermore, overexpression of MUC1 significantly (P<0.05) attenuated the activation of caspase-3 and poly (ADP-ribose) polymerase in response to irradiation exposure. Mechanistically, MUC1 inhibited irradiation-induced apoptosis through activation of janus kinase 2 (JAK2) and STAT3, and induction of anti-apoptotic proteins induced myeloid leukemia cell differentiation protein Mcl-1 (Mcl-1) and BCL2 like 1 (Bcl-xL). Small hairpin RNA-mediated knockdown of STAT3 or MUC1 resensitized MUC1-overexpressing cells to irradiation-induced apoptosis, which was accompanied by reduced expression of Bcl-xL and Mcl-1. Collectively, MUC1 contributes to radioresistance of HCC cells likely through activation of the JAK2/STAT3 signaling pathway and thus represents a potential target for improving radiotherapy against HCC.

show abstract

MUC1 induces drug resistance in pancreatic cancer cells via upregulation of multidrug resistance genes

Cited by 139 publications

References 28 publications

TGF-β-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3

TGF-β-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3

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

Mucin 1 promotes radioresistance in hepatocellular carcinoma cells through activation of JAK2/STAT3 signaling

Contact Info

Product

Resources

About