Pei-Ni Chen

Sunitinib resistance contributes to poor outcomes in advanced renal cell carcinoma (RCC). This study investigated the anti‐metastatic effects and underlying mechanisms of melatonin in sunitinib‐resistant (SR)‐RCC. Melatonin significantly inhibited the migration and invasion of A498‐SR and Caki‐1‐SR cells. SR‐RCC cells exhibited elevated CTSD expression, impaired endoplasmic reticulum (ER) stress signaling with reduced GRP78 and IRE1α, and enhanced p38 MAPK activation, all of which were reversed by melatonin. Silencing p38 MAPK further potentiated the inhibitory effects of melatonin on cell migration and invasion. Mechanistically, CTSD expression was regulated through both GRP78/p38 MAPK‐mediated ER stress. In vivo , melatonin markedly reduced lung metastasis of Caki‐1‐SR cells without causing significant toxicity to major organs. Collectively, these findings demonstrate that melatonin inhibited the metastatic potential of SR‐RCC by decreasing CTSD expression, restoring ER stress response, and decreasing p38 MAPK expression, supporting its potential as an anti‐metastatic therapeutic agent for SR‐RCC

Osteosarcoma is the most common primary malignant bone tumor and is associated with a high mortality rate due to its pronounced metastatic potential. Although tricin has been proposed as a chemosensitizer in various malignancies, its anti‐metastatic effect in osteosarcoma remains poorly characterized. This study investigated whether tricin suppresses metastasis in human osteosarcoma cells and explored the underlying molecular mechanisms. Our results revealed that tricin significantly inhibited the migration and invasion of U2OS and Saos‐2 osteosarcoma cells and downregulated ZNF503 expression at both the mRNA and protein levels. Similarly, siRNA‐mediated knockdown of ZNF503 suppressed cell migration, as confirmed by immunofluorescence analysis. Tricin treatment also reduced phosphorylation of PI3K and Akt, without affecting the activation of ERK1/2, JNK1/2, or p38. Additionally, intracellular levels of PIP3 were diminished following tricin exposure. Notably, the Akt activator SC‐79 significantly reversed tricin‐induced suppression of both ZNF503 expression and cell migration in U2OS and Saos‐2 cells. In conclusion, these findings suggest that ZNF503 inhibits osteosarcoma cell motility via the PI3K–PIP3–Akt signaling axis and that tricin exerts anti‐metastatic effects by targeting this pathway. Tricin may therefore represent a promising therapeutic agent for inhibiting osteosarcoma metastasis.

Apoptosis is a regulated process of programed cell death that removes damaged ells. GO-Y078, a new curcumin analog, has been studied in the oncology field and shown to exert anti-proliferative and anti-angiogenic effects in multiple tumor types. However, its detailed signaling mechanisms and functional effects in human cervical cancer have not been clarified. Herein, GO-Y078 was employed to examine the anti-cancer mechanism in cervical cancer cells. GO-Y078 reduced the cell viability and elicited chromatin condensation and apoptotic cells of human cervical SiHa and HeLa cancer cells. Active PARP and active caspase-9, -8, and -3 were involved in GO-Y078-stimulated apoptosis. GO-Y078 also elevated phosphorylation of mitogen-activated protein kinase (MAPK) pathway. Co-treatment with GO-Y078 and either the ERK inhibitor U0126 or the p38 inhibitor SB203580 significantly reduced GO-Y078-induced activation of caspase-9, -8, and -3. In conclusion, GO-Y078 is a potential therapeutic candidate that induces apoptotic cell death in cervical cancer cells through phosphorylation-dependent activation of MAPK signaling followed by caspase activation.

Osteosarcoma is a cancer associated with a guarded prognosis. Various compounds can induce apoptosis in osteosarcoma cells. Theaflavin-3,3′-digallate (TF3) has been demonstrated to alter cell growth and induce apoptosis in various cancer cells. The present study investigated the apoptotic effect of TF3 on osteosarcoma cells. It further explored key apoptotic pathways activated by TF3. Viability of 143B and U2OS osteosarcoma cells after TF3 treatment was assessed. The effects of TF3 on key apoptotic pathways were analyzed. Furthermore, a xenograft mouse model of osteosarcoma was established for in vivo experiments. The results indicated that TF3 significantly reduced the viability of 143B and U2OS cells. Western blotting revealed that TF3 upregulated the expression of cleaved caspase-3 and cleaved caspase-9 in osteosarcoma cells. In addition, TF3 increased the levels of phosphorylated histone H2Ax, Bax, Bak1, and cytochrome c, while reducing the levels of Mcl-1 and survivin in osteosarcoma cells. Furthermore, TF3 significantly reduced the average tumor volume in the xenograft model. Overall, this study suggests that TF3 induces apoptosis in osteosarcoma cells, primarily by regulating the caspase pathway.

Invasiveness and epithelial–mesenchymal transition (EMT) are main patterns of metastatic disease, which is the major cause cancer‐related mortality in human malignant melanoma cells. Tea and its consumption extract are associated with a lower risk of several types of cancer and have anti‐inflammatory and antioxidative biological effects. However, the anti‐EMT and anti‐cancer stemness effect of black tea ethanol extracts (BTEE) in human melanoma remain poorly understood. In this study, the effects of BTEE‐reduced invasiveness, EMT, and cancer stemness were evaluated in human A 375 and A2058 melanoma cells. BTEE inhibited the activity of u‐PA, migration, and invasiveness by repressing p‐FAK signaling pathway. BTEE affected the EMT by downregulating the expression of β‐catenin, N‐cadherin, fibronectin, vimentin, and Twist‐1. BTEE also reduced tumor necrosis factor‐alpha (TNF‐α)‐induced invasiveness and cancer stemness characteristics in vitro. The growth of melanoma in nude mice xenograft model showed that BTEE suppressed A 375 tumor growth in vivo.

Gossypol, a natural polyphenolic compound, possesses antivirus activity and induces cell death of different types of tumors. However, the efficacy of gossypol on lung carcinoma metastases and epithelial to mesenchymal transition remains unknown. The aim of the present work was to determine the cellular and molecular mechanism of the anti‐cancer and anti‐metastatic efficacies of gossypol on human lung carcinoma cells. Gossypol showed a marked suppression of the viability, motility, and invasion in H1299 and A549 cells. Zymography assay showed that gossypol was sufficient to suppress the activities of urokinase‐type plasminogen activator and matrix metalloproteinase‐2. Gossypol reversed TGF‐β‐induced epithelial to mesenchymal transition. Gossypol reduced vimentin, p‐FAK, p‐Src and p‐paxillin. In vivo studies of gossypol were performed using subcutaneous inoculation and tail vein injection of A549 into immunodeficient BALB/c nude mice and severe combined immunodeficient mice.

Deoxyshikonin (DSK) is a biological component derived from Lithospermum erythrorhizon . Although DSK possesses potential anticancer activities, whether DSK exerts anticancer effects on cervical cancer cells is incompletely explored. This study was aimed to investigate the anticancer activity of DSK against cervical cancer cells and its molecular mechanisms. Cell viability was evaluated by MTT assay. Level of phosphorylation and protein was determined using Western blot. Involvement of signaling kinases was assessed by specific inhibitors. Our results revealed that DSK reduced viability of human cervical cell in a dose‐dependent fashion. Meanwhile, DSK significantly elicited apoptosis of HeLa and SiHa cells. Apoptosis microarray was used to elucidate the involved pathways, and the results showed that DSK dose‐dependently diminished cellular inhibitor of apoptosis protein 1 (cIAP1), cIAP2, and XIAP, and induced cleavage of poly(ADP‐ribose) polymerase (PARP) and caspase‐8/9/3. Furthermore, we observed that DSK significantly triggered activation of ERK, JNK, and p38 MAPK (p38), and only inhibition of p38 diminished the DSK‐mediated pro‐caspases cleavage. Taken together, our results demonstrate that DSK has anti‐cervical cancer effects via the apoptotic cascade elicited by downregulation of IAPs and p38‐mediated caspase activation. This suggests that DSK could act as an adjuvant to facilitate cervical cancer management.

Osteosarcoma is a malignant bone tumor affecting adolescents and children. No effective treatment is currently available. Asiatic acid (AA), a triterpenoid compound found in Centella asiatica, possesses anti‐tumor, anti‐inflammatory, and anti‐oxidant properties in various types of tumor cells. This study aims to determine whether AA exerts antitumor effects in human osteosarcoma cells. Our results indicate that AA does not influence the viability, proliferative rate, or cell cycle phase of human osteosarcoma cells under non‐toxic conditions. AA suppressed osteosarcoma cell migration and invasion by down‐regulating matrix metalloproteinase 1 (MMP1) expression. Data in the TNMplot database suggested MMP1 expression was higher in osteosarcoma than in normal tissues, with associated clinical significance observed in osteosarcoma patients. Overexpression of MMP1 in osteosarcoma cells reversed the AA‐induced suppression of cell migration and invasion. AA treatment decreased the expression of specificity protein 1 (Sp1), while Sp1 overexpression abolished the effect of AA on MMP1 expression and cell migration and invasion. AA inhibited AKT phosphorylation, and treatment with a PI3K inhibitor (wortmannin) increased the anti‐invasive effect of AA on osteosarcoma cells via the p‐AKT/Sp1/MMP1 axis. Thus, AA exhibits the potential for use as an anticancer drug against human osteosarcoma.

Cervical cancer has a poor prognosis and is the fourth most common cancer among women. Dihydromyricetin (DHM), a flavonoid compound, exhibits several pharmacological activities, including anticancer effects; however, the effects of DHM on cervical cancer have received insufficient research attention. This study examined the antitumor activity and underlying mechanisms of DHM on human cervical cancer. Our results indicated that DHM inhibits migration and invasion in HeLa and SiHa cell lines. Mechanistically, RNA sequencing analysis revealed that DHM suppressed S100A4 mRNA expression in HeLa cells. Moreover, DHM inhibited the protein expressions of β-catenin and GSK3β through the regulated extracellular-signal-regulated kinase (ERK)1/2 signaling pathway. By using the ERK1/2 activator, T-BHQ, reverted β-catenin and S100A4 protein expression and cell migration, which were reduced in response to DHM. In conclusion, our study indicated that DHM inhibited cell migration by reducing the S100A4 expression through the ERK1/2/β-catenin pathway in human cervical cancer cell lines.