CCR4-NOT transcription complex subunit 2 (CNOT2), a subunit of the CCR4-NOT complex, has been described in cancer progression. The CNOT complex plays an important role in multiple cellular functions. Recent studies in our laboratory showed that CNOT2 promotes breast cancer cell proliferation and angiogenesis. In addition, CNOT2 signals are critically related to apoptosis induced by atorvastatin in lung cancer cells. Furthermore, depletion of CNOT2 was shown to enhance the antitumor effect of midline 1 interacting protein 1 (MID1IP1) depletion, thus inhibiting c-Myc expression in liver cancer cells. However, the molecular mechanisms related to its oncogenic role remain unclear. Herein, for the first time, we report that CNOT2 inhibition can induce apoptosis in colorectal cancer cells by activating p53. Inhibition of CNOT2 markedly induced apoptosis in various cancer cells like that of the wild-type p53. Furthermore, inhibition of CNOT2 elongated p53 s half-life. Previously, our laboratory demonstrated that MID1IP1 promoted colocalization with c-Myc mediated by CNOT2. Interestingly, inhibition of CNOT2 cannot induce p53 expression without MID1IP1 or apoptosis in cancer cells. In conclusion, our results demonstrate that CNOT2 inhibition induces apoptosis through MID1IP1 by activating p53.

Obesity is a risk factor for metabolic diseases including type 2 diabetes, nonalcoholic steatohepatitis (NASH), heart diseases, and cancer. This study aimed to investigate the anti-obesity effect of Polygalin C (PC) isolated from Polygala japonica Houtt. in 3T3-L1 adipocytes. Based on Oil Red O assay results, PC significantly decreased lipid accumulation compared to the control. We found that PC suppressed adipogenesis transcription factors including peroxisome proliferator-activated receptor γ (PPAR γ) and CCAAT/enhancer-binding protein (C/EBP) α, and lipogenic factors such as sterol regulatory element-binding protein 1c (SREBP 1c) and fatty acid synthase (FAS), in 3T3-L1 adipocytes using Western blotting and real-time polymerase chain reaction (PCR). Moreover, PC inhibited the differentiation of 3T3-L1 cells by regulating the AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) and mitogen-activated protein kinase/protein kinase B (MAPK/Akt) signaling pathways. Additionally, we confirmed that PC inhibited early adipogenesis factors C/EBP β and C/EBP δ. Therefore, PC inhibited adipogenesis and lipogenesis in vitro. Thus, PC appears to exert potential therapeutic effects on obesity by suppressing lipid metabolism.

Colorectal cancer cell (CRC) is the fourth most common cancer in the world. There are several chemotherapy drugs available for its treatment, though they have side effects. Cycloastragenol (CY) is a compound from Astragalus membranaceus (Fisch.) Bge known to be effective in aging, anti-inflammatory, anticancer, and anti-heart failure treatments. Although many studies have demonstrated the functions of CY in cancer cells, no studies have shown the effects of p53 in colon cancer cells. In this study, we found that CY reduces the viability of colon cancer cells in p53 wild-type cells compared to p53 null cells and HT29. Furthermore, CY induces apoptosis by p53 activation in a dose- and time-dependent manner. And it was confirmed that it affects the L5 gene related to p53. Additionally, CY enhanced p53 expression compared to when either doxorubicin or 5-FU was used alone. Altogether, our findings suggest that CY induces apoptosis via p53 activation and inhibits the proliferation of colon cancer cells. In addition, apoptosis occurs in colon cancer cells due to other factors. Moreover, CY is expected to have a combined effect when used together with existing treatments for colon cancer in the future.

Bitter taste receptors (TAS2Rs) are G protein-coupled receptors localized in the taste buds of the tongue. They may also be present in non-lingual organs, including the brain, lung, kidney, and gastrointestinal (GI) tract. Recent studies on bitter taste receptor functions have suggested TAS2Rs as potential therapeutic targets. The human bitter taste receptor subtype hTAS2R50 responds to its agonist isosinensetin (ISS). Here, we demonstrated that, unlike other TAS2R agonists, isosinensetin activated hTAS2R50 as well as increased Glucagon-like peptide 1 (GLP-1) secretion through the G_βγ-mediated pathway in NCI-H716 cells. To confirm this mechanism, we showed that ISS increased intracellular Ca²⁺ and was suppressed by the IP₃R inhibitor 2-APB as well as the PLC inhibitor U73122, suggesting that TAS2Rs alters the physiological state of enteroendocrine L cells in a PLC-dependent manner. Furthermore, we demonstrated that ISS upregulated proglucagon mRNA and stimulated GLP-1 secretion. ISS-mediated GLP-1 secretion was suppressed in response to small interfering RNA-mediated silencing of G_α-gust and hTAS2R50 as well as 2-APB and U73122. Our findings improved the understanding of how ISS modulates GLP-1 secretion and indicates the possibility of using ISS as a therapeutic agent in the treatment of diabetes mellitus.

Timosaponin A3 (TA3), extracted from the rhizome of Anemarrhenaasphodeloides Bunge, has been reported to affect various diseases, such as cancer, Alzheimer’s disease, and allergies. However, the underlying molecular mechanisms and impacts are largely unknown. In the present study, we hypothesized that TA3 induces apoptosis through the inhibition of c-Myc expression via CNOT2 or MID1IP1 in HCT116. An MTT assay and colony formation assay were used to measure cell viability and proliferation. The protein expression of apoptotic markers and oncogenes was measured using immunoblotting and immunofluorescence assays. The interaction between MID1IP1 and c-Myc was confirmed by performing an immunoprecipitation assay. TA3 markedly inhibited colon cancer cell proliferation. Consistently, TA3 regulated the apoptotic proteins pro-PARP and caspase 3. TA3 inhibited the half-life of c-Myc and suppressed its expression in response to serum stimulation. In addition, TA3 enhanced the apoptotic effects of doxorubicin and 5-FU in colon cancer cells. Altogether, our results reveal a mechanism by which TA3 induces apoptosis through inhibiting c-Myc expression via CNOT2 or MID1IP1 in HCT116, which may help in the development of new therapies for colon cancer based on TA3 in the future.