Curcumin, as a pro-apoptotic agent, is extensively studied to inhibit tumor cell growth of various tumor types. Previous work has demonstrated that curcumin inhibits cancer cell growth by targeting multiple signaling transduction and cellular processes. However, the role of curcumin in regulating cellular bioenergetic processes remains largely unknown. Western blotting and qRT-PCR were performed to analyze the protein and mRNA level of indicated molecules, respectively. RTCA, CCK-8 assay, nude mice xenograft assay, and in vivo bioluminescence imaging were used to visualize the effects of curcmin on gastric cancer cell growth in vitro and in vivo. Seahorse bioenergetics analyzer was used to investigate the alteration of oxygen consumption and aerobic glycolysis rate. Curcumin significantly inhibited gastric tumor cell growth, proliferation and colony formation. We further investigated the role of curcumin in regulating cellular redox homeostasis and demonstrated that curcumin initiated severe cellular apoptosis via disrupting mitochondrial homeostasis, thereby enhancing cellular oxidative stress in gastric cancer cells. Furthermore, curcumin dramatically decreased mtDNA content and DNA polymerase γ (POLG) which contributed to reduced mitochondrial oxygen consumption and aerobic glycolysis. We found that curcumin induced POLG depletion via ROS generation, and POLG knockdown also reduced oxidative phosphorylation (OXPHOS) activity and cellular glycolytic rate which was partially rescued by ROS scavenger NAC, indiating POLG plays an important role in the treatment of gastric cancer. Data in the nude mice model verified that curcumin treatment significantly attenuated tumor growth in vivo. Finally, POLG was up-regulated in human gastric cancer tissues and primary gastric cancer cell growth was notably suppressed due to POLG deficiency. Together, our data suggest a novel mechanism by which curcumin inhibited gastric tumor growth through excessive ROS generation, resulting in depletion of POLG and mtDNA, and the subsequent disruption of cellular bioenergetics.

Hepatocellular carcinoma (HCC) is a common cancer type throughout the world. Due to the high occurrence rate and mortality, liver cancer is one of the leading causes of cancer associated death. With the development of monoclonal antibodies and immunotherapy, the mortality of HCC cancer patients has reduced. However, the recurrence and outcomes of patients remain poor. Therefore, there is an urgent need to develop more effective drugs for HCC therapy. WZ35, a novel curcumin derivative, exhibits potential anti-tumor activity in gastric cancer cells by regulating ROS dependent JNK activation and ER stress. Here, we evaluated the tumor suppressive activity of WZ35 in hepatocellular carcinoma in vitro and in vivo. CCK-8 was used to detect cell viability with or without curcumin or WZ35; cell apoptosis was determined by flow cytometry analysis; GFP-LC3 plasmids were used to investigate the level of autophagy-associated LC3; siRNA transfection was applied to silence endogenous YAP; and western blot was performed to detect the alteration of indicated molecules. Bioinformatics analysis and IHC assay were applied to evaluate the YAP level in normal and liver cancer tissues. In this study, we found that WZ35 effectively suppresses HCC cancer cell growth in vitro and in vivo by promoting cell apoptosis. Importantly, downregulation of YAP contributes to WZ35 caused autophagy inhibition which is different from that of curcumin. We also confirmed that WZ35 is more effective at suppressing HCC cell growth in vivo. Finally, we confirmed that YAP was significantly overexpressed in liver cancer tissues. Collectively, these data indicate that WZ35 could be considered as a promising compound for HCC therapy.

Tumor metastasis is the leading cause of cancer death; due to the progress made in the elucidation of the mechanism of cancer cell metastasis, there is hope for patients with severe stages of cancer. Curcumin, as a novel anti-cancer drug, has been applied in cancer therapy; however, the toxicity of curcumin hinders its application. Herein, we constructed a novel derivative, WZ35, and evaluated its metastatic inhibition properties in vitro and in vivo. CCK-8 assay was performed to evaluate the tumor suppressive activity of WZ35. Cell apoptosis was detected by flow cytometry analysis. Transwell cell migration assay and RTCA were used to detect cell migration in mock and WZ35-treated cells. Western blotting was performed to analyze molecular alteration with different treatments. In this study, we found that curcumin and its derivative WZ35 could dramatically suppress proliferation, invasion, and migration of the hepatocellular HCCLM3, HepG2, and Huh7 cancer cells. Moreover, the cancer cell metastatic markers MMP-2, MMP-9, and N-cadherin were decreased, and E-cadherin was up-regulated. In addition, our data show that WZ35 promotes ROS-dependent JNK activation that is essential for WZ35-caused cell metastasis suppression. Moreover, the NAC and JNK inhibitor SP600125 could dramatically reverse WZ35-caused MMP-2, MMP-9, and N-cadherin reduction and E-cadherin up-regulation. We have also found that WZ35 exhibits powerful anti-metastasis activity of HCCLM3 in vivo. In conclusion, our data indicated that WZ35 could be a candidate for the treatment of metastatic liver cancer patients.

As increases in hepatocyte growth factor/scatter factor (HGF/SF) induce retinal pigment epithelial (RPE) migration and proliferation into the vitreous cavity and contribute to proliferative vitreoretinopathy (PVR) development, we determined if changes in miR-182 expression affect such behavioral changes. We found that miR-182 expression was less in PVR clinical samples than in primary RPE cells whereas c-Met was upregulated. Ectopic miR-182 inhibited RPE cell proliferation, cell cycle, and migration. Bioinformatic analysis identified c-Met as a miR-182 target, which was confirmed with the luciferase reporter assay. Transfection of miR-182 into RPE cells induced c-Met downregulation, which led to reduced cell proliferation and migration through declines in p-Akt formation. MiR-182 downregulation along with c-Met upregulation in PVR tissues suggest that these two opposing effects play important roles in PVR development. As ectopic miR-182 expression suppressed RPE cell proliferation and migration, strategies to selectively upregulate miR-182 expression in a clinical setting may provide a novel option to treat this disease.

Background At present, immunotherapy has become an established treatment for cancer. Recently, we have realized that tumor metabolism has a huge impact on the shaping of immune reactivity in the tumor microenvironment (TME). Exploration of the tumor metabolic and immunocellular response reveals metabolic vulnerability as a therapeutic window for intervention to enhance immunotherapy. The clinical significance of glycolysis and its role in tumor-immune evolution have not been fully explored. Understanding the relationships between glycolysis, TME evolution and disease progression is of great significance for optimizing immunotherapy of liver cancer. Methods A glycolysis-related biomarker signature was initially identified in transcriptomic data within The Cancer Genome Atlas (TCGA, n=424). Predicted overall survival (OS) for the gene signature in the GSE54236 dataset (n=161) and our HCC cohort (n=132) was subsequently independently verified. The relative number of immune cells in the microenvironment was calculated using CIBERSORT. CCK-8, IHC, Transwell and Seahorse were used to assess the effects of a 3-gene signature on the malignant phenotype of liver cancer. Results A 3-gene signature of glycolysis significantly associated with poor OS was identified. Based on a multi-omics research strategy, we found the 3-gene signature was closely related to the evolution of liver cancer TME and disease progression, and was associated with liver cancer mutation load and immune evolution. High-risk patients have inhibition and depletion of the immune TME and immune escape through antigen presentation inhibition. Remarkably, the 3-gene signature can predict the clinical outcomes of HCC patients with different clinical subtypes. Conclusions Our investigation of the 3-gene signature provided evidence for tumor metabolism-immune co-evolution along HCC progression. The 3-gene signature for stratification of liver cancer risk has robust predictive power, both at the RNA and protein levels.