Abstract
A selective inhibitor of SKP2 E3 ligase impairs cancer stem cell self-renewal and tumor growth.
Major finding: A selective inhibitor of SKP2 E3 ligase impairs cancer stem cell self-renewal and tumor growth.
Mechanism: Inactivation of SKP2 induces p53-independent senescence and apoptosis and suppresses glycolysis.
Impact: Pharmacologic blockade of SKP2 may eliminate cancer stem cells and overcome chemoresistance.
S-phase kinase-associated protein 2 (SKP2), which functions as an F-box protein as part of the SKP1–Cullin 1–F-box (SCF) E3 ubiquitin ligase complex, promotes the degradation of cell-cycle inhibitory proteins such as p27 and stimulates ubiquitination and activation of AKT signaling. In addition, SKP2 is upregulated in many human cancers and is required for tumorigenesis, implicating SKP2 as a potential therapeutic target. To identify small-molecule inhibitors of SKP2, Chan and colleagues performed high-throughput in silico screening of an in-house chemical library and discovered a compound that potently and specifically inhibited SKP2 but not other F-box proteins. This compound disrupted the interaction of SKP2 with SKP1 in the SCF complex via binding to the SKP2 F-box domain, in particular residues Trp97 and Asp98, resulting in inhibition of SKP2 E3 ligase activity. Treatment with the SKP2 inhibitor impaired the proliferation of a wide range of cancer cell lines, including prostate and lung cancer cells, without significantly affecting the viability of normal cells. Furthermore, administration of the SKP2-targeting compound reduced p27 degradation, downregulated AKT signaling, and inhibited prostate and lung tumor growth in vivo. This antitumorigenic effect was mediated by induction of apoptosis and p53-independent cellular senescence and suppression of AKT-driven glycolysis in cancer cell lines, similar to the effects of Skp2 deficiency. Intriguingly, depletion or pharmacologic inhibition of SKP2 also diminished the accumulation and self-renewal potential of prostate cancer stem cells (CSC), likely via suppression of AKT-mediated glycolysis and stimulation of senescence, and enhanced the sensitivity of prostate cancer cells to chemotherapeutic drugs. These findings validate SKP2 as a cancer drug target and suggest that pharmacologic SKP2 inactivation may limit tumor progression and overcome chemoresistance via elimination of CSCs.
