Yan Li

Extracellular signal-regulated kinase 1/2 (ERK1/2), a key effector involved in cell proliferation, differentiation, and apoptosis, is frequently dysregulated in colorectal cancer (CRC) tumorigenesis and confers extensive therapeutic resistance, with the mechanism to be elucidated. Deubiquitinases (DUBs) catalyze the removal of ubiquitin from substrates and result in altered protein stability, activity, relocalization, or interaction; DUBs have been shown to be closely related to tumorigenesis and are thus attractive drug targets. Ubiquitin-specific protease 22 (USP22) is involved in the occurrence, proliferation, and metastasis of CRC, but the underlying mechanism remains unclear. Here, we report that USP22 expression is correlated with ERK1/2 expression in CRCs. USP22 specifically interacted with ERK1/2 and stabilized it by removing the K48 polyubiquitin chains, thereby activating the ERK signaling pathway to promote CRC. Moreover, we identified ACT001 as a novel USP22 inhibitor, and ACT001 induced substantial ERK1/2 ubiquitination and its subsequent degradation, efficiently suppressing the growth of CRC cells in vitro and in vivo by targeting USP22. Overall, this study revealed the mechanism underlying the role of hyperregulated ERK1/2 in CRC development, providing further insights into the pathology of CRC and the potential applicability of USP22-ERK1/2 as a therapeutic target in CRC.

Hematological malignancies, such as leukemia and multiple myeloma, are heterogeneous blood diseases that affect blood, lymphoid and other related tissues. Ciclopirox olamine (CPX), which is an antifungal agent, was identified as a promising anti-cancer candidate drug recently, especially in hematologic malignancy. However, CPX resistance in hematologic malignancy and the underlying molecular mechanisms are largely unknown. Our present study found that different leukemia cells exhibited different apoptotic responses to CPX. CPX effectively induced mitochondrial-mediated apoptosis in adult acute myeloid leukemia OCI-AML2 cells. However, in human chronic myelogenous leukemia K562 cells, CPX induced little apoptosis. Further study showed that CPX inhibited autophagy in OCI-AML2 cells, but induced autophagy in K562 cells. Notably, compared with CPX alone, the combination of CPX with the autophagy inhibitor chloroquine (CQ) or Bafilomycin A1 (Baf-A1) significantly enhanced pro-apoptotic activity of CPX, suggesting that CPX-induced autophagy is cytoprotective in K562 cells. Mechanism study showed that CPX induced autophagy by activating AMP-activated protein kinase (AMPK)/Unc-51 like autophagy activating kinase 1 (ULK1) signaling. Ectopic expression of dominant negative AMPKα or pharmacological inhibition of AMPK with its inhibitor compound C partially prevented from CPX inducing autophagy and re-sensitized K562 cells to CPX-induced apoptosis. Taken together, our present study demonstrates that AMPK-ULK1-mediated autophagy protects human chronic myelogenous leukemia K562 cells from CPX-induced apoptosis. To improve the clinical therapeutic efficacy of CPX in chronic myelogenous leukemia, the combination therapy of CQ and CPX might be a worthwhile alternative option.

Natural product tanshinone I exhibits weak potency and poor drug-like properties, which have restricted its clinical development as an anticancer agent. Herein, twenty novel tanshinone I-pyridinium salt derivatives and a pyridinium salt precursor were designed and synthesized, and their antitumor activities were evaluated. Among these tanshinone I-pyridinium salts, compound a4, bearing a 4-bromobenzoylmethyl substituent at the N-1 position of the pyridine ring, showed the most potent cytotoxicity against breast cancer (MDA-MB-231), hepatocellular carcinoma (HepG2), and prostate cancer (22RV1) cell lines, with IC₅₀ values of 1.40–1.63 μM. Preliminary mechanistic studies suggest that a4 targets PI3Kα with the IC₅₀ of 9.24 ± 0.20 μM and exerts effective inhibition of the phosphorylation of key PI3K/Akt/mTOR signaling proteins. Besides, a4 significantly downregulates the expression of the immune checkpoint protein PD-L1, indicating its potential to activate tumor immunity. These findings demonstrate that tanshinone I-pyridinium salt derivative a4 is a novel PI3Kα inhibitor, providing a solid foundation for further development of antitumor agents. Graphical Abstract

Due to limited drug efficacy and drug resistance, it is urgent to explore effective anti-liver cancer drugs. Repurposing drugs is an efficient strategy, with advantages including reduced costs, shortened development cycles, and assured safety. In this study, we adopted a synergistic approach combining computational and experimental methods and identified the antibacterial drug thiostrepton (TST) as a candidate for an anti-liver cancer drug. Although the anti-tumor capabilities of TST have been reported, its role and underlying mechanisms in hepatocellular carcinoma (HCC) remain unclear. TST was found here to inhibit the proliferation of HCC cells effectively, arresting the cell cycle and inducing cell apoptosis, as well as suppressing the cell migration. Further, our findings revealed that TST induced mitochondrial impairment, which was demonstrated by destroyed mitochondrial structures, reduced mitochondria, and decreased mitochondrial membrane potential (MMP). TST caused the production of reactive oxygen species (ROS), and the mitochondrial impairment and proliferation inhibition of HCC cells were completely restored by the ROS scavenger N-acetyl-L-cysteine (NAC). Moreover, we discovered that TST induced mitophagy, and autophagy inhibition effectively promoted the anti-cancer effects of TST on HCC cells. In conclusion, our study suggests TST as a promising candidate for the treatment of liver cancers, and these findings provide theoretical support for the further development and potential application of TST in clinical liver cancer therapy.

The aberrant activation of the Wnt/β-catenin signaling pathway is closely associated with the development of various carcinomas, especially colorectal cancers (CRCs), where adenomatous colorectal polyposis (APC) mutations are the most frequently observed, which limits the anti-tumor efficiency of inhibitors targeting the upstream of Wnt/β-catenin pathway. The anti-tumor activity of the naturally occurring alkaloid cepharanthine (CEP) extracted from the plant Stephania cepharantha Hayata has been reported in various types of tumors. We previously observed that its derivatives inhibited the Wnt/β-catenin signaling in liver cancer; however, the specific mechanism remains unknown. In this study, we confirmed CEP can effectively inhibit APC-mutant CRC cell lines (SW480, SW620, LoVo) through disturbing of the Wnt/β-catenin signaling and elucidated the underlying mechanisms. Here, we demonstrate that CEP attenuates the Wnt/β-catenin signaling by decreasing the β-catenin, subsequently impeding the proliferation of APC-mutant CRCs. Moreover, CEP induced β-catenin transcription inhibition rather than the instability of β-catenin protein and mRNA contributes to reduction of β-catenin. Taken together, our findings identify CEP as the first β-catenin transcriptional inhibitor in the modulation of Wnt/β-catenin signaling and indicate CEP as a potential therapeutic option for the treatment of APC-mutated CRCs. Graphical Abstract

Phosphoinositide 3-kinase (PI3Ks) are lipid kinases widely involved in cell proliferation, metastasis and differentiation. Constitutive activation of the PI3K/Akt/mTOR signaling are well confirmed in colorectal cancers (CRCs). In this study, we identified isopropyl 9-ethyl-1-(naphthalen-1-yl)-9 H-pyrido[3,4-b] indole-3-carboxylate (Z86), as a novel PI3Kα inhibitor with the IC₅₀ value of 4.28 µM. The binding of Z86 to PI3Kα was further confirmed with DARTS and CETSA assay. Immunofluorescence analysis and western blotting data demonstrated that Z86 effectively attenuated PI3K/AKT pathway. Z86 caused dramatic proliferation inhibition of CRCs through G0/G1 cycle arrest rather than apoptosis induction. Besides, the migration of CRCs was also relieved by Z86. The present study not only identified Z86 as a novel PI3Kα inhibitor with potent inhibitory efficiency on PI3K-mediated CRCs growth and migration, but also elucidated a reasonable molecular mechanism of Z86 in the Wnt signaling pathway inhibition. Graphical Abstract