Targeting the ubiquitin pathway for cancer treatment

Abstract

Proteasome-mediated degradation is a common mechanism by which cells renew their intracellular proteins and maintain protein homeostasis. In this process, the E3 ubiquitin ligases are responsible for targeting specific substrates (proteins) for ubiquitin-mediated degradation. However, in cancer cells, the stability and the balance between oncoproteins and tumor suppressor proteins are disturbed in part due to deregulated proteasome-mediated degradation. This ultimately leads to either stabilization of oncoprotein(s) or increased degradation of tumor suppressor(s), contributing to tumorigenesis and cancer progression. Therefore, E3 ubiquitin ligases including the SCF types of ubiquitin ligases have recently evolved as promising therapeutic targets for the development of novel anti-cancer drugs. In this review, we highlighted the critical components along the ubiquitin pathway including E1, E2, various E3 enzymes and DUBs that could serve as potential drug targets and also described the available bioactive compounds that target the ubiquitin pathway to control various cancers.

USP22 acts as an oncogene by regulating the stability of cyclooxygenase-2 in non-small cell lung cancer

“…The ubiquitin proteasome system is one of the mechanisms responsible for protein clearance, which among other functions, serves to prevent the activation of molecular signaling pathways such as those leading to cancer development [20]. Deubiquitinating enzymes (DUBs) catalyze the removal of ubiquitin from proteins and are subdivided into cysteine proteases and metalloproteases.…”

CD166 positively regulates MCAM via inhibition to ubiquitin E3 ligases Smurf1 and βTrCP through PI3K/AKT and c-Raf/MEK/ERK signaling in Bel-7402 hepatocellular carcinoma cells

“…The E3 ligase-mediated ubiquitination is relied on the interaction between E3 ligase and its specific substrate [22,23]. To confirm the interaction between βTrCP, Smurf1 and MCAM, we performed reciprocal coimmunoprecipitation (Co-IP) experiments and found that exogenous MCAM-HA could be readily pulled down by βTrCP-FLAG or Smurf1-FLAG and vice versa (Fig.…”

Inhibition of SCF ubiquitin ligases by engineered ubiquitin variants that target the Cul1 binding site on the Skp1–F-box interface

“…Fbl1 (Skp2) eliminates the CDK inhibitor p27 and is a well-validated target for cancer treatment; several small-molecule inhibitors of Skp2 show activity in preclinical models (reviewed in ref. 5). However, given poorly defined roles for many F-box proteins and the functional complexity observed for those with characterized roles, further studies are required to gauge the therapeutic potential of this E3 family (4).…”