Functional Interaction of Tumor Suppressor DLC1 and Caveolin-1 in Cancer Cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2012-09, Vol.72 (17), p.4405-4416
• Main Authors: XIAOLI DU, XIAOLAN QIAN, PAPAGEORGE, Alex, SCHETTER, Aaron J, VASS, William C, XI LIU, BRAVERMAN, Richard, ROBLES, Ana I, LOWY, Douglas R
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Caveolin 1 - genetics; Caveolin 1 - metabolism; Cell Line, Tumor; Cell Movement - genetics; Cell Proliferation; Female; Gene Deletion; Gene Expression Regulation, Neoplastic; GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - metabolism; Humans; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Medical sciences; Mice; Mice, Nude; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - mortality; Pharmacology. Drug treatments; Prognosis; Protein Binding; Protein Interaction Domains and Motifs; Protein Transport; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-12-0777

Deleted in liver cancer 1 (DLC1), a tumor suppressor gene frequently inactivated in non-small cell lung cancer (NSCLC) and other malignancies, encodes a multidomain protein with a RhoGTPase-activating (RhoGAP) domain and a StAR-related lipid transfer (START) domain. However, no interacting macromolecule has been mapped to the DLC1 START domain. Caveolin-1 (CAV-1) functions as a tumor suppressor in most contexts and forms a complex with DLC1. Here, we have mapped the region of DLC1 required for interaction with CAV-1 to the DLC1 START domain. Mutation of the DLC1 START domain disrupted the interaction and colocalization with CAV-1. Moreover, DLC1 with a START domain mutation failed to suppress neoplastic growth, although it negatively regulated active Rho. CAV-1 and DLC1 expression levels were correlated in two public datasets of NSCLC lines and in two independent publicly available mRNA expression datasets of NSCLC tumors. Clinically, low DLC1 expression predicted a poor clinical outcome in patients with lung cancer. Together, our findings indicate that complex formation between the DLC1 START domain and CAV-1 contributes to DLC1 tumor suppression via a RhoGAP-independent mechanism, and suggest that DLC1 inactivation probably contributes to cancer progression.