The mechanism of the growth-inhibitory effect of coxsackie and adenovirus receptor (CAR) on human bladder cancer : A functional analysis of CAR protein structure

• Published in: Cancer research (Chicago, Ill.) Vol. 61; no. 17; pp. 6592 - 6600
• Main Authors: OKEGAWA, Takatsugu, PONG, Rey-Chen, YINGMING LI, BERGELSON, Jeffrey M, SAGALOWSKY, Arthur I, HSIEH, Jer-Tsong
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-09-2001
• Subjects: Adenoviridae - physiology; Aged; Aged, 80 and over; Biological and medical sciences; Cell Adhesion - physiology; Cell Aggregation - physiology; Cell Division - physiology; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Coxsackie and Adenovirus Receptor-Like Membrane Protein; Cyclin-Dependent Kinase Inhibitor p21; Cyclins - biosynthesis; Female; Fundamental and applied biological sciences. Psychology; Growth Inhibitors - biosynthesis; Growth Inhibitors - genetics; Growth Inhibitors - physiology; Humans; Male; Middle Aged; Molecular and cellular biology; Nuclear Proteins - biosynthesis; Receptors, Virus - biosynthesis; Receptors, Virus - genetics; Receptors, Virus - physiology; RNA, Messenger - genetics; RNA, Messenger - metabolism; Structure-Activity Relationship; Transfection; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - metabolism; Urinary Bladder Neoplasms - pathology; Urinary Bladder Neoplasms - virology; Antineoplastic agent; Cell proliferation; Coxsackievirus; Adenoviridae; Cell function; Molecular structure; Picornaviridae; Gene product; Tumoral tissue; Enterovirus; Transfection; Urinary bladder; Established cell line; Tumor progression; Mechanism of action; Tumor cell; Biological receptor; Human; Urinary system disease; Urinary tract disease; Malignant tumor; Gene expression; In vitro; Protein; Virus; Infection; Sensitivity resistance; Bladder disease
• ISSN: 0008-5472; 1538-7445

The coxsackie and adenovirus receptor (CAR) is identified as a high-affinity receptor for adenovirus type 5. We observed that invasive bladder cancer specimens had significantly reduced CAR mRNA levels compared with superficial bladder cancer specimens, which suggests that CAR may play a role in the progression of bladder cancer. Elevated CAR expression in the T24 cell line (CAR-negative cells) increased its sensitivity to adenovirus infection and significantly inhibited its in vitro growth, accompanied by p21 and hypophosphorylated retinoblastoma accumulation. Conversely, decreased CAR levels in both RT4 and 253J cell lines (CAR-positive cells) promoted their in vitro growth. To unveil the mechanism of action of CAR, we showed that the extracellular domain of CAR facilitated intercellular adhesion. Furthermore, interrupting intercellular adhesion of CAR by a specific antibody alleviates the growth-inhibitory effect of CAR. We also demonstrated that both the transmembrane and intracellular domains of CAR were critical for its growth-inhibitory activity. These data indicate that the cell-cell contact initiated by membrane-bound CAR can elicit a negative signal cascade to modulate cell cycle regulators inside the nucleus of bladder cancer cells. Therefore, the presence of CAR cannot only facilitate viral uptake of adenovirus but also inhibit cell growth. These results can be integrated to formulate a new strategy for bladder cancer therapy.