Maintenance of cancer stemness by miR-196b-5p contributes to chemoresistance of colorectal cancer cells via activating STAT3 signaling pathway Maintenance of cancer stemness by miR-196b-5p contributes to chemoresistance of colorectal cancer cells via activating STAT3 signaling pathway

The study of metabolism provides important information for understanding the biological basis of cancer cells and the defects of cancer treatment. Disorders of polyamine metabolism is a common metabolic change in cancer. With the deepening of understanding of polyamine metabolism, including molecular functions and changes in cancer, polyamine metabolism as a new anti-cancer strategy has become the focus of attention. There are many kinds of polyamine biosynthesis inhibitors and transport inhibitors, but not many drugs have been put into clinical application. Recent evidence shows that polyamine metabolism plays essential roles in remodeling the tumor immune microenvironment (TIME), particularly treatment of DFMO, an inhibitor of ODC, alters the immune cell population in the tumor microenvironment. Tumor immunosuppression is a major problem in cancer treatment. More and more studies have shown that the immunosuppressive effect of polyamines can help cancer cells to evade immune surveillance and promote tumor development and progression. Therefore, targeting polyamine metabolic pathways is expected to become a new avenue for immunotherapy for cancer.

Breast cancer is a leading cause of mortality among women with cancer worldwide. Quercetin‑3‑methyl ether, a natural compound occurring in various plants, has been indicated to have potent anticancer activity. Breast cancer cell growth and survival were examined by CCK‑8 and colony formation assay, whilst cell cycle and apoptosis were determined by flow cytometry. Cell invasion and migration were assessed by wound‑healing assay and Transwell assay. Cancer stem cell formation was analyzed by mammosphere formation assay and related signaling pathways were detected by western blotting. In the present study, it was observed that treatment with quercetin‑3‑methyl ether significantly inhibited cell growth, induced apoptosis and cell cycle arrest at the G2‑M phase, and suppressed invasion and migration in human breast cancer cells, including the triple negative MDAMB‑231 cell line, and the estrogen receptor‑positive/progesterone receptor‑positive/human epidermal growth factor receptor 2‑negative MCF‑7 and T47D cell lines. This compound also markedly suppressed the epithelial‑mesenchymal transition process as evidenced by the upregulated expression of E‑cadherin, and the concomitant downregulated expression of vimentin and MMP‑2. Furthermore, it was demonstrated that quercetin‑3‑methyl ether treatment inhibited mammosphere formation and the expression of the stemness‑related genes, SRY‑box 2 and Nanog. Mechanistically, this compound decreased the expression of Notch1, and induced the phosphorylation of phosphoinositide 3‑kinase (PI3K) and Akt. It also attenuated the human insulin growth factor 1‑induced phosphorylation of PI3K, Akt and glycogen synthase kinase β. Additionally, the combination of quercetin‑3‑methyl ether and a secretase inhibitor (DAPT) exhibited additive suppression of the expression of Notch1, PI3K, Akt and mammalian target of rapamycin and a more marked inhibitory effect on cell proliferation and colony formation compared with either drug alone. Treatment with quercetin‑3‑methyl ether alone markedly suppressed the levels of tri‑methyl histone H3 (Lys27), but had no effect on the expression of enhancer of zeste homolog 2. Overall, these findings indicated that quercein‑3‑methyl ether may be a potential therapeutic compound for the treatment of triple negative and hormone‑sensitive breast cancer.

Photodynamic therapy (PDT) is a noninvasive, highly selective approach to the treatment of tumors. However, its therapeutic effect is limited by long‐lasting skin phototoxicity. Therefore, to compromise this shortcoming, it is preferable to deliver photosensitizers selectively to tumor cells with the aid of antibodies specific against tumor‐associated antigens. Cancer/testis antigens 83 (CT83), also called KK‐LC‐1 or CXorf61, recognized by cytotoxic T lymphocytes (CTL), has become a promising target for immunotherapy. Herein, we developed and characterized a novel mouse CT83 mAb 7G4 with a high affinity with Gallium (III) 5, 10, 15‐tris (ethoxycarbonyl) corrole (1‐Ga), a new and promising photosensitizer in PDT. The enzyme‐linked immunosorbent assay (ELISA), flow cytometry and cytotoxicity activity assays revealed that 7G4‐1‐Ga was able to recognize human CT83 with high specificity. Furthermore, 7G4‐1‐Ga showed greater cytotoxicity to CT83‐expressing human cancer cells in vitro than 1‐Ga. These results suggest that the antibody‐conjugated photosensitizer between anti‐CT83 mAb and 1‐Ga may have a good application in PDT, where the destruction of CT83‐expressing tumor is required.

Eukaryotic initiation factor 5A2 (eIF5A2) is overexpressed in many types of cancer, and spermidine-mediated eIF5A hypusination (eIF5A^hpu) appears to be essential to most of eIF5A’s biological functions, including its important role in regulating cancer cell proliferation, epithelial–mesenchymal transition (EMT), and cancer stem cell (CSC) properties as well as immune cell functions. Here we investigated the role of eIF5A^hpu in the growth of oral squamous cell carcinoma cells (OSCCs) and OSCC-induced polarization of M2-like tumor-associated macrophages (TAMs). TCGA dataset analysis revealed an overall upregulation in the mRNA expression of eIF5A2 and several key enzymes involved in polyamine (PA) metabolism in HNSCC, which was confirmed by Western blot and IHC studies. Blocking eIF5A^hpu by GC-7 but not the upstream key enzyme activities of PA metabolism, remarkably inhibited cell proliferation and the expression of EMT- and CSC-related genes in OSCC cells. In addition, blocking eIF5A^hpu robustly inhibited OSCC-induced M2-like TAM polarization in vitro. More Importantly, blocking eIF5A^hpu dramatically retarded tumor growth and infiltration/polarization of M2-like TAM in a syngeneic orthotopic murine tongue SCC model. Thus, eIF5A^hpu plays dual functions in regulating tumor cell growth and polarization of M2-TAMs in OSCC.