Targeting MUC1-C inhibits the AKT-S6K1-elF4A pathway regulating TIGAR translation in colorectal cancer.
Colorectal cancer is third most common malignancy and is the second most common cause of cancer-related death. The MUC1 heterodimeric protein is aberrantly overexpressed in colorectal cancer and has been linked to poor outcomes in this disease. Here, we investigate the effects of the MUC1-C subunit inhibitor (GO-203), which disrupts MUC1-C homo-oligomerization, on human colorectal cancer cells.



TIGAR mRNA level was determined using qRT-PCR. Western blotting was used to measure TIGAR protein level and AKT-mTOR-S6K1 pathways. Reactive oxygen species and apoptosis were measured by flow cytometry. Effect of MUC1-C peptide, GO-203 was studied on colorectal xenograft tumors. Immunohistochemistry was utilized for TIGAR staining.



Treatment of MUC1-overexpressing SKCO-1 and Colo-205 colon cancer cells with GO-203 was associated with downregulation of the TP53-inducible glycolysis and apoptosis regulator (TIGAR) protein. TIGAR promotes the shunting of glycolytic intermediates into the pentose phosphate pathway and thus is of importance for maintaining redox balance. We show that GO-203-induced suppression of TIGAR is mediated by inhibition of AKT and the downstream mTOR pathway. The results also demonstrate that targeting MUC1-C blocks eIF4A cap-dependent translation of TIGAR. In concert with these results, GO-203-induced suppression of TIGAR was associated with decreases in GSH levels. GO-203 treatment also resulted in increases in reactive oxygen species (ROS) and loss of mitochondrial transmembrane potential. Consistent with these results, GO-203 inhibited the growth of colon cancer cells in vitro and as xenografts in nude mice. Inhibition of MUC1-C also downregulated TIGAR expression in xenograft tissues.



These findings indicate that MUC1-C is a potential target for the treatment of colorectal cancer. Colorectal cancer patients who overexpress MUC1-C may be candidates for treatment with the MUC1-C inhibitor alone or in combination therapy with other agents.
Colorectal Research Center, Department of Surgery, King Khalid University Hospital College of Medicine, King Saud University, PO BOX 7805 (37), Riyadh, Saudi Arabia. arehan@ksu.edu.sa.
Rehan
R
Ahmad
Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, MA, 02215, USA.
Maroof
M
Alam
Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, MA, 02215, USA.|Present Address: Department of Urology, Keio University School of Medicine, Shinanomachi 35, Shinzyuyku-ku, Tokyo, 160-8582, Japan.
Masanori
M
Hasegawa
Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, MA, 02215, USA.|Present Address: Department of Urology, Keio University School of Medicine, Shinanomachi 35, Shinzyuyku-ku, Tokyo, 160-8582, Japan.
Yasumitsu
Y
Uchida
Colorectal Research Center, Department of Surgery, King Khalid University Hospital College of Medicine, King Saud University, PO BOX 7805 (37), Riyadh, Saudi Arabia.
Omar
O
Al-Obaid
Genus Oncology, Boston, MA, 02115, USA.
Surender
S
Kharbanda
Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, MA, 02215, USA.
Donald
D
Kufe
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D018396:Mucin-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D010455:Peptides / Q000494:pharmacology; D010744:Phosphoric Monoester Hydrolases; D014176:Protein Biosynthesis / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
C582521:(arginine)9-cysteinyl-glutaminyl-cysteinyl-arginyl-arginyl-lysyl-asparagine; D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; C111931:ELF4 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C060192:MUC1 protein, human; D018396:Mucin-1; D010455:Peptides; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D010744:Phosphoric Monoester Hydrolases; C512708:TIGAR protein, human; D005978:Glutathione
AKT; Colorectal cancer; MUC1-C; S6K1; TIGAR