AGM-1470

Breast cancer (BC) is a frequent malignancy that endangers women's health, and its fatality rate ranks 1st among female malignancies. Research has shown that rutaecarpine (RUT), which is a Chinese herbal medicine, blocks the proliferation of cancer cells by a variety of molecular mechanisms. However, the possible effects and mechanism of RUT in the autophagy and angiogenesis of BC cells has not been clearly articulated.

MiR-149-3p and S100A4 expression levels were assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and the optimal concentration and time of RUT was confirmed by Cell Counting Kit-8 (CCK-8) assays of the BC cells. After treatment, changes in cell proliferation and the cell cycle were evaluated by CCK-8 assays, clone formation assays, and flow cytometry, and the levels of apoptosis, autophagy, and angiogenesis-related proteins were identified by Western blot. The targeted regulation of miR-149-3p on S100A4 was also examined by luciferase reporter assays.

We found that RUT inhibited cell growth and upregulated miR-149-3p in MDA-MB-231 cells. In relation to the biological function activity, RUT attenuated proliferation and angiogenesis, and induced cell-cycle arrest and autophagy by miR-149-3p in the MDA-MB-231 cells. Additionally, miR-149-3p downregulated S100A4 by targeting binding to S100A4, and S100A4 was required for miR-149-3p to play a role in BC progression. We also discovered that an autophagy agonist (rapamycin) or an angiogenesis inhibitor (TNP-470) changed BC progression mediated by the RUT/miR-149-3p/S100A4 axis.

RUT blocks the malignant behaviors of BC cells through the miR-149-3p/S100A4 axis and thus alters autophagy and angiogenesis. Thus, the RUT-mediated miR-149-3p/S100A4 axis might be an underlying therapeutic agent and target for BC.

Pancreatic ductal adenocarcinoma (PDA) is an aggressive metastatic cancer with a very low survival rate. This tumor is hypovascularized and characterized by severe hypoxic regions, yet these regions are not impeded by the oxidative stress in their microenvironment. PDA's high resilience raises the need to find new effective therapeutic targets. This study investigated the suitability of methionine aminopeptidase 2 (MetAp2), a metallopeptidase known to play an important role in tumor progression, as a new target for treating PDA. In our examination of patient-derived PDA tissues, we found that MetAp2 is highly expressed in metastatic regions compared with primary sites. At the cellular level, we found that the basal expression levels of MetAp2 in pancreatic cancer cells were higher than its levels in endothelial cells. Pancreatic cancer cells showed a significant suppression of proliferation in a dose-dependent manner upon exposure to TNP-470, a selective MetAp2 inhibitor. In addition, a significant reduction in glutathione (GSH) levels - known for its importance in alleviating oxidative stress - was detected in all treated cells, suggesting a possible anti-cancer activity mechanism that would be feasible for treating highly hypoxic PDA tumors. Furthermore, in an orthotopic pancreatic cancer murine model, systemic oral treatment with a MetAp2 inhibitor significantly reduced tumors' growth. Taken together, our findings indicate that MetAp2 enhances tumor sensitivity to hypoxia and may provide an effective target for treating hypoxic tumors with high expression levels of MetAp2.