Dependence on the MUC1-C oncoprotein in non-small cell lung cancer cells.

Abstract

Non-small cell lung cancer (NSCLC) cells are often associated with constitutive activation of the phosphoinositide 3-kinase (PI3K) → Akt → mTOR pathway. The mucin 1 (MUC1) heterodimeric glycoprotein is aberrantly overexpressed in NSCLC cells and induces gene signatures that are associated with poor survival of NSCLC patients. The present results show that the MUC1 C-terminal subunit (MUC1-C) cytoplasmic domain associates with PI3K p85 in NSCLC cells. We show that inhibition of MUC1-C with cell-penetrating peptides blocks this interaction with PI3K p85 and suppresses constitutive phosphorylation of Akt and its downstream effector, mTOR. In concert with these results, treatment of NSCLC cells with the MUC1-C peptide inhibitor GO-203 was associated with downregulation of PI3K → Akt signaling and inhibition of growth. GO-203 treatment was also associated with increases in reactive oxygen species (ROS) and induction of necrosis by a ROS-dependent mechanism. Moreover, GO-203 treatment of H1975 (EGFR L858R/T790M) and A549 (K-Ras G12S) xenografts growing in nude mice resulted in tumor regressions. These findings indicate that NSCLC cells are dependent on MUC1-C both for activation of the PI3K → Akt pathway and for survival.

• Authors: Deepak Raina, Michio Kosugi, Rehan Ahmad, Govind Panchamoorthy, Hasan Rajabi, Maroof Alam, Takeshi Shimamura, Geoffrey I Shapiro, Jeffrey Supko, Surender Kharbanda, Donald Kufe
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 10 Issue 5 Pg. 806-16 (May 2011) ISSN: 1538-8514 [Electronic] United States
• PMID: 21421804 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• (arginine)9-cysteinyl-glutaminyl-cysteinyl-arginyl-arginyl-lysyl-asparagine
• Antineoplastic Agents
• GO 201
• Mucin-1
• Peptides
• Reactive Oxygen Species
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt

Topics

• Amino Acid Sequence
• Animals
• Antineoplastic Agents (pharmacology)
• Carcinoma, Non-Small-Cell Lung (pathology)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Female
• HEK293 Cells
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Molecular Sequence Data
• Mucin-1 (genetics, metabolism)
• Peptides (pharmacology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Protein Binding (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays