A Minimal Fragment of MUC1 Mediates Growth of Cancer Cells

Mahanta, Sanjeev K.; Fessler, Shawn P.; Park, Jaehong; Bamdad, Cynthia

doi:10.1371/journal.pone.0002054

Cited by 69 publications

(94 citation statements)

References 35 publications

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“…Of the 1.3 million tumors, diagnosed in the US each year, over 60% show tumor-associated aberrant overexpression of MUC1 (Ren et al, 2004). Reaserches previously showed that ligand-induced dimerization of the extracellular domain of MUC1 induced ERK2 phosphorylation, cell proliferation and survival (Hikita et al, 2008;Mahanta et al, 2008). Thus, in trastuzumab resistant cells, MUC1 could function independently by homodimerization to increase cell growth and inhibit apoptosis, thereby countering the growth inhibitory effects of trastuzumab.…”

Section: Discussionmentioning

confidence: 99%

Effect of MUC1 siRNA on Drug Resistance of Gastric Cancer Cells to Trastuzumab

Deng¹,

Jing²,

Meng³

2013

Asian Pacific Journal of Cancer Prevention

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Trastuzumab is the first molecular targeting drug to increase the overall survival rate in advanced gastric cancer. However, it has also been found that a high intrinsic or primary trastuzumab resistance exists in some proportion of gastric cancer patients. In order to explore the mechanism of resistance to trastuzumab, firstly we investigated the expression of MUC1 (membrane-type mucin 1) in gastric cancer cells and its relationship with drug-resistance. Then using gene-silencing, we transfected a siRNA of MUC1 into drug-resistant cells. The results showed the MKN45 gastric cell line to be resistant to trastuzumab, mRNA and protein expression of MUC1 being significantly upregulated. After transfection of MUC1 siRNA, protein expression of MUC1 in MKN45cells was significantly reduced. Compared with the junk transfection and blank control groups, the sensitivity to trastuzumab under MUC1 siRNA conditions was significantly increased. These results imply that HER2-positive gastric cancer cell MKN45 is resistant to trastuzumab and this resistance can be cancelled by silencing expression of the MUC1 gene.

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Section: Discussionmentioning

confidence: 99%

Effect of MUC1 siRNA on Drug Resistance of Gastric Cancer Cells to Trastuzumab

Deng¹,

Jing²,

Meng³

2013

Asian Pacific Journal of Cancer Prevention

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“…Recent evidence suggests that Nm23-H1 can bind a cleaved form of Mucin1 called MUC1*, which is present on the surface of many cancer cell lines and on pluripotent stem cells (20,21). The binding of Nm23-H1 to MUC1* was reported to result in dimerization of MUC1*, and subsequent activation of the MAPK pathway to increase proliferation of the breast cancer cell line T47D (20).…”

Section: Introductionmentioning

confidence: 99%

Nm23-H1 Indirectly Promotes the Survival of Acute Myeloid Leukemia Blast Cells by Binding to More Mature Components of the Leukemic Clone

et al. 2011

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Nm23-H1 plays complex roles in the development of diverse cancers including breast carcinoma, high-grade lymphomas, and acute myeloid leukemia (AML). In the case of AML and lymphomas, serum Nm23-H1 protein is elevated with the highest levels correlating with poorest prognosis. A recent study identified that this association is most likely causal in AML and that Nm23-H1 acts as an AML cell survival factor. In this study, we report heterogeneity in the ability of AML samples to bind and respond to Nm23-H1, and we offer evidence that binding is essential for improved survival. Further, we show that the subset of AMLs that bind Nm23-H1 do not do so through the putative Nm23-H1 receptor MUC1*. Although rNm23-H1 promoted the survival of the most primitive blasts within responding AMLs, it was not these cells that actually bound the protein. Instead, rNm23-H1 bound to more mature CD34 lo /CD34 À and CD11b þ cells, revealing an indirect survival benefit of Nm23-H1 on primitive blasts. In support of this finding, the survival of purified blast cells was enhanced by medium conditioned by more mature cells from the clone that had been stimulated by rNm23-H1. Levels of interleukin 1b (IL1b) and IL6 in rNm23-H1 conditioned medium mirrored the potency of the conditioned media to promote blast cell survival. Furthermore, Nm23-H1 expression was significantly associated with IL1b and IL6 expression in primary uncultured AML samples. These findings have implications for the role of Nm23-H1 in AML and its use as a prognostic marker. Additionally, they offer the first evidence of novel cross-talk between cell populations within the tumor clone. Cancer Res; 71(3); 1177-86. Ó2010 AACR.

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“…This result is expected on the basis of many reports that the hMUC-1 marker is expressed on the cancer stem cells as well as the more mature epithelial neoplastic cells. [24][25][26] Clinical trials involving i.p. injection of therapy sensitization adenoviral vectors have been carried out successfully.…”

Section: Discussionmentioning

confidence: 99%

“…One such approach is immunotherapy. As the MUC-1 antigen has been found on the cancer stem cells or tumorinitiating cells as well as on the majority of the more mature cells of epithelial neoplasms, [24][25][26] we tested if the hMUC-1/ecdCD40 L VPPP vaccine when combined with the AdCMVCDIRESE1A targeted chemotherapy [5][6][7][8] could produce a decrease in the level of the CD44 +…”

Section: Cd24mentioning

confidence: 99%

Addition of adenoviral vector targeting of chemotherapy to the MUC-1/ecdCD40L VPPP vector prime protein boost vaccine prolongs survival of mice carrying growing subcutaneous deposits of Lewis lung cancer cells

et al. 2010

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We studied the effect of adding chemotherapy or vector targeted chemotherapy to the administration of an Ad-sighMUC-1/ecdCD40L adenoviral vector prime-hMUC-1/ ecdCD40L protein boost cancer vaccine (designated hMUC-1/ecdCD40L VPPP vaccine), which were administered to test mice 10 days following subcutaneous (s.c.) inoculation of 500 000 Lewis Lung Carcinoma cells, at a time when the average volume of the s.c. tumors was 50 cu mm. The survival of hMUC-1/ecdCD40L VPPP vaccine-treated mice was twice as long as untreated mice. Addition of vector-targeted chemotherapy (AdCMVCDIRESE1A/5FC) to the hMUC-1/ ecdCD40L VPPP vaccine 10 days after tumor inoculation significantly (P ¼ 0.0062) prolonged the survival of the test mice over administration of the hMUC-1/ecdCD40L VPPP vaccine alone or the control mice (Po0.00001). Interestingly, the combination of the AdCMVCDIRESE1A/5FC vector-targeted chemotherapy to the hMUC-1/ecdCD40L VPPP vaccine decreased the levels of CD44 + CD24 À cells in s.c. deposits of the human MUC-1-positive Lewis Lung Cancer cell line (LL2/ LL1hMUC-1) by 20 fold. These results suggest that the addition of vector-targeted chemotherapy to an adenoviral-based cancer vaccine is a strategy that deserves further testing.

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A Minimal Fragment of MUC1 Mediates Growth of Cancer Cells

Cited by 69 publications

References 35 publications

Effect of MUC1 siRNA on Drug Resistance of Gastric Cancer Cells to Trastuzumab

Effect of MUC1 siRNA on Drug Resistance of Gastric Cancer Cells to Trastuzumab

Nm23-H1 Indirectly Promotes the Survival of Acute Myeloid Leukemia Blast Cells by Binding to More Mature Components of the Leukemic Clone

Addition of adenoviral vector targeting of chemotherapy to the MUC-1/ecdCD40L VPPP vector prime protein boost vaccine prolongs survival of mice carrying growing subcutaneous deposits of Lewis lung cancer cells

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