Inhibition of MUC1‐C regulates metabolism by AKT pathway in esophageal squamous cell carcinoma

Gongsun, Xin; Zhao, Yongqiang; Jiang, Bin; Xin, Zhongwei; Shi, Mo; Song, Lingyun; Qin, QiMing; Wang, Qiang; Liu, XiangYan

doi:10.1002/jcp.27863

Cited by 24 publications

(15 citation statements)

References 55 publications

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“…Previous studies have shown that overexpression of MUC1 leads to the upregulation of signaling molecules involved in PI3K/Akt/mTOR pathway. Genetical depletion or drug inhibition of MUC1 would otherwise inhibit signal transduction of PI3K/Akt/mTOR [40,41]. Our study showed that MUC1 overexpression promoted the activation of PI3K/Akt, which was consistent with previous results.…”

Section: Discussionsupporting

confidence: 93%

Overexpression of Mucin 1 Suppresses the Therapeutical Efficacy of Disulfiram against Canine Mammary Tumor

Zhao

Lin

et al. 2020

Animals

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Mucin 1 (MUC1), a transmembrane protein, is closely associated with the malignancy and metastasis of canine mammary tumors; however, the role of overexpressed MUC1 in the development of cancer cells and response to drug treatment remains unclear. To address this question, we developed a new canine mammary tumor cell line, CIPp-MUC1, with an elevated expression level of MUC1. In vitro studies showed that CIPp-MUC1 cells are superior in proliferation and migration than wild-type control, which was associated with the upregulation of PI3K, p-Akt, mTOR, Bcl-2. In addition, overexpression of MUC1 in CIPp-MUC1 cells inhibited the suppressing activity of disulfiram on the growth and metastasis of tumor cells, as well as inhibiting the pro-apoptotic effect of disulfiram. In vivo studies, on the other side, showed more rapid tumor growth and stronger resistance to disulfiram treatment in CIPp-MUC1 xenograft mice than in wild-type control. In conclusion, our study demonstrated the importance of MUC1 in affecting the therapeutical efficiency of disulfiram against canine mammary tumors, indicating that the expression level of MUC1 should be considered for clinical use of disulfiram or other drugs targeting PI3K/Akt pathway.

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Section: Discussionsupporting

confidence: 93%

Overexpression of Mucin 1 Suppresses the Therapeutical Efficacy of Disulfiram against Canine Mammary Tumor

Zhao

Lin

et al. 2020

Animals

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“…GO‐203 blocks this CQC motif, and inhibits the function of MUC1‐C as an intracellular signaling protein 30 . GO‐203 was shown previously to be effective at inhibiting cell proliferation in an in vitro assay and in xenograft models of breast, esophageal, lung, and colorectal carcinomas 31‐34 . The present study demonstrated that the targeting of MUC1‐C with GO‐203 inhibited p‐AKT in UC cells, which suppressed the downstream target, MDR1.…”

Section: Discussionsupporting

confidence: 61%

Role of the MUC1‐C oncoprotein in the acquisition of cisplatin resistance by urothelial carcinoma

et al. 2020

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Mucin 1 C-terminal subunit (MUC1-C) has been introduced as a key regulator for acquiring drug resistance in various cancers, but the functional role of MUC1-C in urothelial carcinoma (UC) cells remains unknown. We aimed to elucidate the molecular mechanisms underlying the acquisition of cisplatin (CDDP) resistance through MUC1-C oncoprotein in UC cells. MUC1-C expression was examined immunohistochemically in tumor specimens of 159 UC patients who received CDDP-based perioperative chemotherapy. As a result, moderate to high MUC1-C expression was independently associated with poor survival in UC patients. Using human bladder cancer cell lines and CDDP-resistant (CR) cell lines, we compared the expression levels of MUC1-C, multiple drug resistance 1 (MDR1), the PI3K-AKT-mTOR pathway, and x-cystine/glutamate transporter (xCT) to elucidate the biological mechanisms contributing to the acquisition of chemoresistance. MUC1-C was strongly expressed in CR cell lines, followed with MDR1 expression via activation of the PI3K-AKT-mTOR pathway. MUC1-C also stabilized the expression of xCT, which enhanced antioxidant defenses by increasing intracellular glutathione (GSH) levels. MUC1 down-regulation showed MDR1 inhibition along with PI3K-AKT-mTOR pathway suppression. Moreover, it inhibited xCT stabilization and resulted in significant decreases in intracellular GSH levels and increased reactive oxygen species (ROS) generation. The MUC1-C inhibitor restored sensitivity to CDDP in CR cells and UC murine xenograft models. In conclusion, we found that MUC1-C plays a pivotal role in the acquisition of CDDP resistance in UC cells, and therefore the combined treatment of CDDP with a MUC1-C inhibitor may become a novel therapeutic option in CR UC patients.

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“…GO-201 was shown to be effective against human prostate, breast, pancreatic and esophageal squamous cell carcinoma tumor xenograft models at different dosedependent schedules, whereas CP-1 had no apparent effect on tumor growth or histology 30,41,45,46 . GO-201 and GO-203 both contain the CQCRRKN sequence, block MUC1-C dimerization and have similar dose-dependent activity in vitro and in vivo 28,42,47,48 . In addition, treatment of tumors with GO-203 encapsulated in nanoparticles (GO-203/NPs) has demonstrated dose-dependent activity 49 .…”

Section: Muc1-c Drives Pathways Associated With Lineage Plasticitymentioning

confidence: 99%

MUC1-C regulates lineage plasticity driving progression to neuroendocrine prostate cancer

et al. 2020

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Neuroendocrine prostate cancer (NEPC) is an aggressive malignancy with no effective targeted therapies. The oncogenic MUC1-C protein is overexpressed in castration-resistant prostate cancer (CRPC) and NEPC, but its specific role is unknown. Here, we demonstrate that upregulation of MUC1-C in androgen-dependent PC cells suppresses androgen receptor (AR) axis signaling and induces the neural BRN2 transcription factor. MUC1-C activates a MYC→BRN2 pathway in association with induction of MYCN, EZH2 and NE differentiation markers (ASCL1, AURKA and SYP) linked to NEPC progression. Moreover, MUC1-C suppresses the p53 pathway, induces the Yamanaka pluripotency factors (OCT4, SOX2, KLF4 and MYC) and drives stemness. Targeting MUC1-C decreases PC self-renewal capacity and tumorigenicity, suggesting a potential therapeutic approach for CRPC and NEPC. In PC tissues, MUC1 expression associates with suppression of AR signaling and increases in BRN2 expression and NEPC score. These results highlight MUC1-C as a master effector of lineage plasticity driving progression to NEPC.

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Inhibition of MUC1‐C regulates metabolism by AKT pathway in esophageal squamous cell carcinoma

Cited by 24 publications

References 55 publications

Overexpression of Mucin 1 Suppresses the Therapeutical Efficacy of Disulfiram against Canine Mammary Tumor

Overexpression of Mucin 1 Suppresses the Therapeutical Efficacy of Disulfiram against Canine Mammary Tumor

Role of the MUC1‐C oncoprotein in the acquisition of cisplatin resistance by urothelial carcinoma

MUC1-C regulates lineage plasticity driving progression to neuroendocrine prostate cancer

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