Pyrvinium Pamoate Induces Cell Apoptosis and Autophagy in Colorectal Cancer.

BACKGROUND/AIM: In earlier research, we demonstrated that pyrvinium pamoate (PP) can effectively inhibit the proliferation and migration of colorectal cancer (CRC) cells. In the current study, we further explore the possibility of PP, as a potential therapeutic drug in the treatment of CRC. MATERIALS AND METHODS: Hoechst 33258 staining, immunofluorescence, and western blotting were used to further investigate the connection between PP and CRC cell apoptosis and autophagy. RESULTS: We found that PP promoted apoptosis and autophagy of CRC cells. At the protein level, the expression of proteins related to the PI3K/mTOR signaling pathway exhibited a negative correlation with the dosage of PP. PP may therefore induce apoptosis and autophagy by inhibiting the PI3K/mTOR signaling pathway. CONCLUSION: Our in vitro experiments demonstrated that PP could inhibit the progression of colorectal cancer cells by inducing apoptosis and autophagy. The detailed mechanism needs further investigation.

BMAL1 promotes colorectal cancer cell migration and invasion through ERK- and JNK-dependent c-Myc expression.

BACKGROUND: Cancer metastasis is still a life threat to patients with colorectal cancer (CRC). Brain and muscle ARNT-like protein 1 (BMAL1) is an important biological proteins that can regulate the behavior of cancer cells and their response to chemotherapy. However, the role of BMAL1 in the tumorigenic phenotype of CRC remains unclear. Here, we aim to investigate the functional role and mechanisms of BMAL1 in CRC. METHODS: The mRNA expression of BMAL1 was studied using the Cancer Genome Atlas (TCGA) databases. The protein level in clinical tissues was confirmed by immunohistochemistry (IHC). The effects of BMAL1 on the epithelial-to-mesenchymal transition (EMT) and proliferation of CRC cell lines (including BMAL1 overexpressed or silencing cells) were studied by Transwell, wound healing, CCK-8 and colony formation experiments. A series of experiments were conducted to demonstrate the mechanisms of BMAL1 regulating EMT and cancer proliferation in vitro and in vivo. RESULTS: We found that BMAL1 expression was closely related to the poor prognosis of CRC. BMAL1 overexpression promoted cell proliferation and migration. Mechanistically, we found that BMAL1 may activate the epithelial-to-mesenchymal transition (EMT) pathway and induce the ß-catenin release further promotes the expression of oncogene c-Myc and the migration of colorectal cells by activating MAPK pathway. However, BMAL1 silencing achieved the opposite effect. In addition, blocking MAPK-signaling pathway with specific inhibitors of ERK1/2 and JNK can also downregulate the expressions of c-Myc in vitro. Taken together, these results suggested that the BMAL1/ c-Myc-signaling pathway may regulate the metastasis of CRC through the JNK/ERK1/2 MAPK-dependent pathway. CONCLUSIONS: Our study showed that BMAL1 promotes CRC metastasis through MAPK-c-Myc pathway. These results deepen our understanding of the relationship between BMAL1 and tumorigenic phenotypes, which may become a promising therapeutic target for BMAL1 overexpressing CRC.

Comparative genomic signatures in young and old Chinese patients with colorectal cancer.

BACKGROUND: Occurrence at a young age is known to be associated with unique clinical features in colorectal cancer (CRC). However, the genomic differences between young and old patients with CRC are not well elucidated and, to the best of our knowledge, have never been investigated in a Chinese population. METHODS: Tumor tissue samples from 29 young (age ≤50 years) and 46 old (age >50 years) patients with CRC were collected. Targeted sequencing of 808 cancer-related genes was conducted to characterize the genomic landscape for Chinese CRC. RESULTS: Overall, mutational profiles exhibited notable differences between the two groups. In particular, APC and PIK3CA mutations were more frequently observed in old patients (p = 0.009 and p = 0.012, respectively), while SMAD4 mutations tended to occur in young patients (p = 0.054). Mutation loci distributions of KRAS in the young cohort differed from those in the old cohort, and a higher frequency of KRAS codon 12 mutations was potentially associated with a young age (p = 0.076). The frequencies of clinically actionable alterations were analyzed by defined age categories, which unveiled a distinctive targeted genomic profile in the young group. Furthermore, among patients with mismatch repair-proficient (pMMR) CRC, tumor mutation burden (TMB) was positively correlated with age (Pearson's r = 0.306, p = 0.011), and genomic alterations associated with high TMB in young patients differentiated from those in old patients. CONCLUSIONS: These findings revealed different molecular characterization between young and old Chinese patients with CRC, which may provide novel insights for the personalized treatment of CRC.

Pyrvinium pamoate inhibits cell proliferation through ROS-mediated AKT-dependent signaling pathway in colorectal cancer.

The use of the anthelmintic drug pyrvinium pamoate (PP) in cancer therapy has been extensively investigated in the last decade. PP has been shown to have an inhibitory effect in colorectal cancer (CRC), but the underlying mechanism remains elusive. We aimed to investigate the antitumor activity and mechanisms of PP in CRC. In the present study, we used CCK-8 assays, colony formation assays, and western blotting to reveal that PP effectively suppressed CRC cell proliferation and the AKT-dependent signaling pathway in a concentration-dependent and time-dependent manner. Flow cytometric analysis and fluorescence microscopy demonstrated that PP increased intracellular reactive oxygen species (ROS) accumulation. We found that the inhibitory effect of PP on cell proliferation and AKT protein expression induced by PP could be partially reversed by N-acetyl-L-cysteine (NAC), an ROS scavenger. In addition, the results also demonstrated that PP inhibited cell migration by modulating epithelial-to-mesenchymal transition (EMT)-related proteins, including E-cadherin and vimentin. In conclusion, our data suggested that PP effectively inhibited cell proliferation through the ROS-mediated AKT-dependent signaling pathway in CRC, further providing evidence for the use of PP as an antitumor agent.

Small molecule 2,3-DCPE induces S phase arrest by activating the ATM/ATR-Chk1-Cdc25A signaling pathway in DLD-1 colon cancer cells.

In our previous study, it was reported that 2[[3-(2,3-dichlorophenoxy)propyl]amino]ethanol (2,3-DCPE) induces apoptosis and cell cycle arrest. The current study aimed to investigate the molecular mechanism involved in 2,3-DCPE-induced S phase arrest. The results demonstrated that 2,3-DCPE upregulated phosphorylated (p-)H2A histone family member X, a biomarker of DNA damage, in the DLD-1 colon cancer cell line. Western blotting revealed that 2,3-DCPE increased the checkpoint kinase (Chk)1 (Ser317 and Ser345) level and decreased the expression of M-phase inducer phosphatase 1 (Cdc25A) in a time-dependent manner. Subsequently, the results demonstrated that the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia and Rad3-related (ATR) inhibitors wortmannin and caffeine had no effect on the cell cycle; however, the inhibitors partially abrogated 2,3-DCPE-induced S phase arrest. Flow cytometry assays revealed that caffeine (2 mM) reduced the proportion of S phase cells from 83 to 39.6% and that wortmannin (500 nM) reduced the proportion of S phase cells from 83 to 48.2%. Furthermore, wortmannin and caffeine inhibited the 2,3-DCPE-mediated phosphorylation of Chk1 and the degradation of Cdc25A. However, these ATM/ATR inhibitors had limited effect on 2,3-DCPE-induced apoptosis. Taken together, the data of the current study indicated that 2,3-DCPE caused DNA damage in colon cancer cells and that 2,3-DCPE-induced S phase arrest was associated with the activation of the ATM/ATR-Chk1-Cdc25A pathway.