|Product-Name:||GO-203 TFA salt|
|Related Cas:||1223466-72-5(free base)|
GO-203 TFA salt(cas 1222186-26-6)cell-penetrating MUC1-C peptide inhibitor.
1. Mol Cancer Res. 2013 Jul;11(7):714-23. doi: 10.1158/1541-7786.MCR-12-0668. Epub
2013 Mar 28.
Oncogenic MUC1-C promotes tamoxifen resistance in human breast cancer.
Kharbanda A(1), Rajabi H, Jin C, Raina D, Kufe D.
(1)Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Tamoxifen resistance of estrogen receptor-positive (ER+) breast cancer cells has
been linked in part to activation of receptor tyrosine kinases, such as HER2, and
the PI3K-AKT pathway. Mucin 1 (MUC1) is aberrantly overexpressed in about 90% of
human breast cancers, and the oncogenic MUC1-C subunit is associated with ERα.
The present studies using HER2 overexpressing BT-474 breast cancer cells, which
are constitutively resistant to tamoxifen, demonstrate that silencing MUC1-C is
associated with (i) downregulation of p-HER2 and (ii) sensitivity to
tamoxifen-induced growth inhibition and loss of clonogenic survival. In contrast,
overexpression of MUC1-C in tamoxifen-sensitive MCF-7 breast cancer cells
resulted in upregulation of p-AKT and tamoxifen resistance. We show that MUC1-C
forms complexes with ERα on the estrogen-responsive promoter of Rab31 and that
MUC1-C blocks tamoxifen-induced decreases in ERα occupancy. MUC1-C also
attenuated tamoxifen-induced decreases in (i) recruitment of the coactivator CREB
binding protein, (ii) Rab31 promoter activation, and (iii) Rab31 mRNA and protein
levels. The importance of MUC1-C is further supported by the demonstration that
targeting MUC1-C with the cell-penetrating peptide inhibitor, GO-203, sensitized
tamoxifen-resistant cells to tamoxifen treatment. Moreover, we show that
targeting MUC1-C in combination with tamoxifen is highly synergistic in the
treatment of tamoxifen-resistant breast cancer cells. Combined, these findings
indicate that MUC1-C contributes to tamoxifen resistance.
2. Genes Cancer. 2011 Jan;2(1):56-64. doi: 10.1177/1947601911405044.
MUC1-C Oncoprotein Blocks Terminal Differentiation of Chronic Myelogenous
Leukemia Cells by a ROS-Mediated Mechanism.
Yin L(1), Kufe D.
(1)Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Chronic myelogenous leukemia (CML) inevitably progresses to a blast phase by
mechanisms that are not well understood. The MUC1-C oncoprotein is expressed in
CML blasts but not chronic phase cells. The present studies demonstrate that
treatment of KU812 and K562 CML cells with a cell-penetrating MUC1-C inhibitor,
designated GO-203, is associated with increases in reactive oxygen species (ROS)
and depletion of glutathione. GO-203 treatment resulted in the complete
downregulation of Bcr-Abl expression and induced cell cycle arrest by a
ROS-mediated mechanism that was blocked by the antioxidant N-acetylcysteine.
Progression of CML to blast crisis has been linked to dysregulation of
Wnt/β-catenin signaling and an arrest of differentiation. The present results
show that inhibition of MUC1-C induces ROS-mediated suppression of β-catenin
expression and induction of a differentiated myeloid phenotype. Our studies also
show that GO-203 treatment is associated with ROS-induced decreases in ATP and
loss of survival by late apoptosis/necrosis. These findings demonstrate that
inhibition of the MUC1-C oncoprotein in CML cells disrupts redox balance and
thereby 1) downregulates expression of both Bcr-Abl and β-catenin and 2) induces
terminal myeloid differentiation by ROS-mediated mechanisms.