MUC1 oncoprotein promotes growth and survival of human multiple myeloma cells

Kawano, Takeshi; Ahmad, Rehan; Nogi, Hiroko; Agata, Naoki; Anderson, Kenneth C.; Küfe, Donald

doi:10.3892/ijo.33.1.153

Cited by 32 publications

(55 citation statements)

References 41 publications

(48 reference statements)

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“…22,23 In concert with MUC1-C-mediated stabilization of b-catenin, silencing MUC1-C in MM cells is associated with decreases in b-catenin and slowing of growth. 24 These and other findings in breast cancer cells 25 have linked MUC1-C to activation of WNT/b-catenin signaling and the induction of WNT target genes. Significantly, the MUC1-C cytoplasmic domain also contains a CQC motif that is necessary for MUC1-C homodimerization and for localization of MUC1-C to the nucleus.…”

Section: Introductionmentioning

confidence: 86%

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: Introductionmentioning

confidence: 86%

MUC1-C drives MYC in multiple myeloma

Tagde

Rajabi

Bouillez

et al. 2016

Blood

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Section: Introductionmentioning

confidence: 99%

“…In MM cells, silencing MUC1-C results in slowing of proliferation, enhanced sensitivity to apoptosis, and increased loss of self-renewal in the response to melphalan and dexamethasone, supporting involvement of MUC1-C in MM cell growth and survival. 22 The MUC1-C subunit cytoplasmic domain includes a CQC motif that is necessary and sufficient for its homodimerization and oncogenic function.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.…”

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confidence: 99%

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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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“…MUC1 is highly expressed on a range of malignancies, including breast, pancreas, ovarian, prostate, and colon carcinomas, as well as on the malignant plasma cell of myeloma (8)(9)(10)(11)(12)(13). Because of this overexpression, MUC1 has been the subject of a great amount of attention, primarily for its potential as a target for tumor-specific therapies.…”

Section: Introductionmentioning

confidence: 99%

Antibody Targeting of Cell-Bound MUC1 SEA Domain Kills Tumor Cells

Pichinuk

Benhar²,

Jacobi³

et al. 2012

Cancer Research

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The cell-surface glycoprotein MUC1 is a particularly appealing target for antibody targeting, being selectively overexpressed in many types of cancers and a high proportion of cancer stem-like cells. However the occurrence of MUC1 cleavage, which leads to the release of the extracellular a subunit into the circulation where it can sequester many anti-MUC1 antibodies, renders the target problematic to some degree. To address this issue, we generated a set of unique MUC1 monoclonal antibodies that target a region termed the SEA domain that remains tethered to the cell surface after MUC1 cleavage. In breast cancer cell populations, these antibodies bound the cancer cells with high picomolar affinity. Starting with a partially humanized antibody, DMB5F3, we created a recombinant chimeric antibody that bound a panel of MUC1 þ cancer cells with higher affinities relative to cetuximab (anti-EGFR1) or tratuzumab (anti-erbB2) control antibodies. DMB5F3 internalization from the cell surface occurred in an efficient temperature-dependent manner. Linkage to toxin rendered these DMB5F3 antibodies to be cytotoxic against MUC1 þ cancer cells at low picomolar concentrations. Our findings show that high-affinity antibodies to cell-bound MUC1 SEA domain exert specific cytotoxicity against cancer cells, and they point to the SEA domain as a potential immunogen to generate MUC1 vaccines. Cancer Res; 72(13); 3324-36. Ó2012 AACR.

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MUC1 oncoprotein promotes growth and survival of human multiple myeloma cells

Cited by 32 publications

References 41 publications

MUC1-C drives MYC in multiple myeloma

MUC1-C drives MYC in multiple myeloma

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

Antibody Targeting of Cell-Bound MUC1 SEA Domain Kills Tumor Cells

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