Abstract
VCP inhibitors promote cancer cell apoptosis via UPR activation and disruption of autophagy.
Major finding: VCP inhibitors promote cancer cell apoptosis via UPR activation and disruption of autophagy.
Mechanism: A covalent inhibitor blocks ATP binding, whereas allosteric inhibitors impair nucleotide turnover.
Impact: Disruption of protein homeostasis via VCP inhibition may be therapeutically beneficial.
Proteasome inhibitors such as bortezomib have shown clinical efficacy, highlighting the sensitivity of cancer cells to disruption of protein degradation and supporting the identification of additional targets that modulate protein homeostasis. Valosin containing protein (VCP) is an essential ATPase that is upregulated in some tumors and functions as a molecular chaperone to promote the degradation of client proteins, including several cancer-related proteins, and to regulate autophagy; however, currently available VCP inhibitors lack specificity and it remains unclear whether VCP is a valid therapeutic target. To address this question, Magnaghi and colleagues performed high-throughput screening and identified specific VCP-targeting compounds, including both covalent and allosteric inhibitors. A covalent VCP inhibitor irreversibly modified cysteine 522 within the active site of VCP, thereby blocking ATP binding and VCP enzymatic activity; mutation of this cysteine residue prevented covalent modification and rescued VCP activity and cell proliferation. In contrast, allosteric VCP inhibitors interacted with a binding site composed of a pocket across the D1 and D2 domains of adjacent subunits within the VCP hexamer and enhanced VCP binding affinity for ADP, suggesting that this class of inhibitors interferes with nucleotide turnover and conformational changes between domains that are necessary for ATP hydrolysis. Importantly, both the covalent inhibitor and a potent, specific allosteric inhibitor reduced the proliferation of a wide range of cancer cells; this antiproliferative activity was mediated by VCP client protein stabilization, accumulation of polyubiquitinated proteins, activation of the unfolded protein response, and interruption of autophagy, resulting in induction of apoptosis upon VCP inhibition, similar to the effects of VCP silencing. These results establish VCP as a druggable target essential for cancer cell growth and support further development of VCP-targeting compounds for cancer therapy.
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