Direct Targeting of the Mucin 1 Oncoprotein Blocks Survival and Tumorigenicity of Human Breast Carcinoma Cells

Raina, Deepak; Ahmad, Rehan; Joshi, Maya Datt; Li, Yin; Wu, Zhiyou; Kawano, Takeshi; Vasir, Baldev; Avigan, David; Kharbanda, Surender; Küfe, Donald

doi:10.1158/0008-5472.can-09-0854

Cited by 136 publications

(231 citation statements)

References 36 publications

(62 reference statements)

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“…26,38 Accordingly, we developed agents, such as the cell-penetrating peptide , that target the CQC motif and block MUC1-C homodimerization ( Figure 1C). 29,39 Treatment of RPMI8226 cells with GO-203, but not with the control peptide CP-2 ( Figure 1C), resulted in the downregulation of MUC1-C expression ( Figure 1D). We also found that suppression of MUC1-C is associated with decreases in MYC mRNA and protein ( Figure 1D, left and right).…”

Section: Muc1-c Induces Myc Expression In MM Cellsmentioning

confidence: 99%

MUC1-C drives MYC in multiple myeloma

Tagde

Rajabi

Bouillez

et al. 2016

Blood

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• MUC1-C induces MYC gene transcription in MM cells.• Targeting MUC1-C downregulates MYC expression and its transcriptional program.Multiple myeloma (MM) cell lines and primary tumor cells are addicted to the MYC oncoprotein for survival. Little is known, however, about how MYC expression is upregulated in MM cells. The mucin 1 C-terminal subunit (MUC1-C) is an oncogenic transmembrane protein that is aberrantly expressed in MM cell lines and primary tumor samples. The present studies demonstrate that targeting MUC1-C with silencing by clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 editing or with the GO-203 inhibitor is associated with downregulation of MYC messenger RNA and protein.The results show that MUC1-C occupies the MYC promoter and thereby activates the MYC gene by a b-catenin/transcription factor 4 (TCF4)-mediated mechanism. In this way, MUC1-C (1) increases b-catenin occupancy on the MYC promoter, (2) forms a complex with b-catenin and TCF4, and, in turn, (3) drives MYC transcription. Analysis of MM cells using quantitative real-time reverse transcription polymerase chain reaction arrays further demonstrated that silencing MUC1-C is associated with downregulation of MYC target genes, including CCND2, hTERT, and GCLC. Analysis of microarray data sets further demonstrated that MUC1 levels positively correlate with MYC expression in MM progression and in primary cells from over 800 MM patients. These findings collectively provide convincing evidence that MUC1-C drives

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Section: Muc1-c Induces Myc Expression In MM Cellsmentioning

confidence: 99%

MUC1-C drives MYC in multiple myeloma

Tagde

Rajabi

Bouillez

et al. 2016

Blood

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“…23,25 Accordingly, cell-penetrating peptides have been developed to target the CQC motif. 26,27 The MUC1-C inhibitory peptides include the MUC1-C CQCRRKN sequence linked to 9 Arg residues for cell transduction, such that binding of the peptide to endogenous MUC1-C blocks its homodimerization. [26][27][28] In particular, MUC1-C inhibitor treatment of MM cells growing in vitro and as tumor xenografts is associated with inhibition of growth and induction of late apoptosis/ necrosis.…”

Section: Introductionmentioning

confidence: 99%

“…[26][27][28] In particular, MUC1-C inhibitor treatment of MM cells growing in vitro and as tumor xenografts is associated with inhibition of growth and induction of late apoptosis/ necrosis.…”

mentioning

confidence: 99%

Targeting MUC1-C is synergistic with bortezomib in downregulating TIGAR and inducing ROS-mediated myeloma cell death

Kufe

Avigan

et al. 2014

Blood

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• Targeting the MUC1-C oncoprotein in MM cells potentiates BTZ-induced downregulation of TIGAR and thereby ROS-mediated death.• Targeting MUC1-C is effective in resensitizing BTZ-resistant MM cells to BTZ and thus represents a potential strategy for combination treatment.The proteosome inhibitor bortezomib (BTZ) induces endoplasmic reticulum and oxidative stress in multiple myeloma (MM) cells. The mucin 1 C-terminal subunit (MUC1-C) oncoprotein is aberrantly expressed in most MM cells, and targeting MUC1-C with GO-203, a cell-penetrating peptide inhibitor of MUC1-C homodimerization, is effective in inducing reactive oxygen species (ROS)-mediated MM cell death. The present results demonstrate that GO-203 and BTZ synergistically downregulate expression of the p53-inducible regulator of glycolysis and apoptosis (TIGAR), which promotes shunting of glucose-6-phosphate into the pentose phosphate pathway to generate reduced glutathione (GSH). In turn, GO-203 blocks BTZ-induced increases in GSH and results in synergistic increases in ROS and MM cell death. The results also demonstrate that GO-203 is effective against BTZ-resistant MM cells. We show that BTZ resistance is associated with BTZ-induced increases in TIGAR and GSH levels, and that GO-203 resensitizes BTZ-resistant cells to BTZ treatment by synergistically downregulating TIGAR and GSH. The GO-203/BTZ combination is thus highly effective in killing BTZ-resistant MM cells. These findings support a model in which targeting MUC1-C is synergistic with BTZ in suppressing TIGARmediated regulation of ROS levels and provide an experimental rationale for combining with BTZ in certain settings of BTZ resistance. (Blood. 2014;123(19):2997-3006) IntroductionMultiple myeloma (MM) is a clonal malignancy of plasma cells that is characterized in part by the abnormal synthesis and secretion of monoclonal immunoglobulins or light chains.1 Cellular homeostasis is dependent on the balanced regulation of protein synthesis and degradation, the latter of which is predominantly mediated by the ubiquitin-proteosome pathway.2 Bortezomib (BTZ) is a reversible inhibitor of the proteosome that is effective in inducing apoptosis of MM cells and is active in the treatment of this disease.1 BTZ has improved response rates of MM patients to induction therapy and is being used as consolidation after frontline treatment or transplantation. 1,3 However, intrinsic and acquired resistance to BTZ represent a challenge for the treatment of MM, which remains an incurable disease.1 BTZ has been shown to activate the unfolded protein response (UPR), a pathway induced by the accumulation of unfolded proteins in the endoplasmic reticulum (ER) and associated with increases in reactive oxygen species (ROS). 4,5 In this way, BTZ treatment of MM cells induces expression of CCAAT/enhancer binding protein-homologous protein (CHOP; GADD153), a key transcription factor that participates in cellular responses to ER and oxidative stress. [6][7][8] The mechanistic basis for BTZ activity has also been attributed...

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“…These findings indicate that up-regulation of C1GALT1 promotes breast tumor growth through modified glycophenotypes of MUC1-N and MUC1-C signaling pathway. An inhibitory small peptide GO-201 specifically targeting the CQC residues of MUC1-C cytoplasmic domain has been well established to prevent MUC1-C dimerization and activation in breast cancer development [29,41]. Indeed, we found that GO-201 significantly suppressed C1GALT1-mediated cell viability and inhibited MUC1-C translocation into the nucleus in T47D and MCF-7 cells.…”

Section: Discussionmentioning

confidence: 66%