Ziliang Wang

Ursolic Acid Inhibits Glycolysis of Ovarian Cancer via KLF5/PI3K/AKT Signaling Pathway

Glycolysis is one of the key metabolic reprogramming characteristics of ovarian cancer. Ursolic Acid (UA), as a natural compound, exerts a beneficial regulatory effect on tumor metabolism. In this study, we have confirmed through RNA-seq analysis and a series of in vitro and in vivo functional experiments that UA significantly inhibits ovarian cancer cell proliferation, promotes tumor apoptosis, and reduces glycolysis levels. Additionally, it demonstrates synergistic therapeutic effects with cisplatin in both in vitro and in vivo experiments. Furthermore, at the molecular level, we found that UA inhibits glycolysis in ovarian cancer by binding to the transcription factor KLF5 and blocking the transcriptional expression of the downstream PI3K/AKT signaling pathway, thereby exerting its therapeutic effect. In conclusion, our research indicates that UA can inhibit the proliferation, apoptosis, and glycolysis levels of ovarian cancer cells through the KLF5/PI3K/AKT signaling axis. Our findings offer a new perspective on the therapeutic application of the natural compound UA in ovarian cancer and support its potential development as a candidate for chemotherapy.

Long non-coding RNA CTSLP8 mediates ovarian cancer progression and chemotherapy resistance by modulating cellular glycolysis and regulating c-Myc expression through PKM2

Abstract Purpose Long non-coding RNAs (lncRNAs) play vital roles in tumor progression and resistance. Ovarian cancer (OC), a common gynecological cancer, is associated with poor prognosis as it can progress to peritoneal metastasis and develop resistance to chemotherapy. This study aimed to examine the role of lncRNAs in the development of chemotherapy resistance in OC. Methods The clinical samples were divided into chemotherapy-sensitive and chemotherapy-resistant groups based on the chemotherapy response at follow-up. The glycolysis levels in the two groups were analyzed using positron emission tomography/computed tomography (PET/CT) scanning and immunohistochemistry. GEO dataset analysis revealed the expression of CTSLP8 in chemotherapy-resistant patients with OC. Two pairs of normal and diamminodichloroplatinum (DDP)-resistant cells were transfected with CTSLP8 overexpression and knockdown constructs to examine the functions of CTSLP8 in the OC cells and elucidate the underlying mechanisms. The in vivo effect of CTSLP8 overexpression and knockdown on the chemotherapy response of tumors was examined using a mouse subcutaneous tumor model. The tissue chips were subjected to fluorescence in situ hybridization and immunohistochemical (IHC) staining to examine the correlation among CTSLP8 expression, DDP resistance, and prognosis in OC. Results The dataset analysis demonstrated that CTSLP8 was upregulated in chemotherapy-resistant tumor tissues. CTSLP8 promoted the proliferation and development of DDP resistance in the OC cells. Moreover, CTSLP8 promoted c-Myc expression by facilitating the binding of PKM2 to the promoter region of c-Myc, thereby upregulating glycolysis. The analysis of tissue chips revealed that the upregulation of CTSLP8 was associated with the development of DDP resistance and poor prognosis in patients with OC. Conclusions These findings indicate that CTSLP8 forms a complex with PKM2 to regulate c-Myc, and this action results in the upregulation of cellular glycolysis, consequently promoting OC progression and development of chemotherapy resistance. Headlights 1. CTSLP8 was upregulated in the chemotherapy-resistant tumor tissues. 2. CTSLP8 promoted the proliferation and cisplatin resistance in the OC cells. 3. CTSLP8 promoted glycolysis by facilitating the binding of PKM2 to the promoter region of c-Myc. 4. Inhibition of CTSLP8 or the combination of c-Myc inhibitors with cisplatin were potential therapeutic strategies for chemotherapy-resistant of OC.

FBP1 regulates proliferation, metastasis, and chemoresistance by participating in C-MYC/STAT3 signaling axis in ovarian cancer

AbstractFructose-1,6-bisphosphatase (FBP1) is a rate-limiting enzyme in gluconeogenesis and an important tumor suppressor in human malignancies. Here, we aimed to investigate the expression profile of FBP1 in ovarian cancer, the molecular mechanisms that regulate FBP1 expression and to examine how the FBP1 regulatory axis contributes to tumorigenesis and progression in ovarian cancer. We showed that FBP1 expression was significantly decreased in ovarian cancer tissues compared with normal ovarian tissues, and low-FBP1 expression predicted poor prognosis in patients with ovarian cancer. The enhanced expression of FBP1 in ovarian cancer cell lines suppressed proliferation and 2-D/3-D invasion, reduced aerobic glycolysis, and sensitized cancer cells to cisplatin-induced apoptosis. Moreover, DNA methylation and C-MYC binding at the promoter inhibited FBP1 expression. Furthermore, through physical interactions with signal transducer and activator of transcription 3 (STAT3), FBP1 suppressed nuclear translocation of STAT3 and exerted its non-metabolic enzymatic activity to induce the dysfunction of STAT3. Thus, our study suggests that FBP1 may be a valuable prognostic predictor for ovarian cancer. C-MYC-dependent downregulation of FBP1 acted as a tumor suppressor via modulating STAT3, and the C-MYC/FBP1/STAT3 axis could be a therapeutic target.

Programmed death ligand‐1 regulates angiogenesis and metastasis by participating in the c‐JUN/VEGFR2 signaling axis in ovarian cancer

Abstract Background Although programmed cell death‐ligand 1 (PD‐L1) plays a well‐known function in immune checkpoint response by interacting with programmed cell death‐1 (PD‐1), the cell‐intrinsic role of PD‐L1 in tumors is still unclear. Here, we explored the molecular regulatory mechanism of PD‐L1 in the progression and metastasis of ovarian cancer. Methods Immunohistochemistry of benign tissues and ovarian cancer samples was performed, followed by migration, invasion, and angiogenesis assays in PD‐L1‐knockdown ovarian cancer cells. Immunoprecipitation, mass spectrometry, and chromatin immunoprecipitation were conducted along with zebrafish and mouse experiments to explore the specific functions and mechanisms of PD‐L1 in ovarian cancer. Results Our results showed that PD‐L1 induced angiogenesis, which further promoted cell migration and invasion in vitro and in vivo of ovarian cancer. Mechanistically, PD‐L1 was identified to directly interact with vascular endothelial growth factor receptor‐2 (VEGFR2) and then activated the FAK/AKT pathway, which further induced angiogenesis and tumor progression, leading to poor prognosis of ovarian cancer patients. Meanwhile, PD‐L1 was found to be regulated by the oncogenic transcription factor c‐JUN at the transcriptional level, which enhanced the expression of PD‐L1 in ovarian cancer. Furthermore, we demonstrated that PD‐L1 inhibitor durvalumab, combined with the antiangiogenic drug, apatinib, could enhance the effect of anti‐angiogenesis and the inhibition of cell migration and invasion. Conclusion Our results demonstrated that PD‐L1 promoted the angiogenesis and metastasis of ovarian cancer by participating in the c‐JUN/VEGFR2 signaling axis, suggesting that the combination of PD‐L1 inhibitor and antiangiogenic drugs may be considered as a potential therapeutic approach for ovarian cancer patients.