Renquan Lu

TPX2 promotes ovarian tumorigenesis by interacting with Lamin A/C and affecting its stability

AbstractObjectiveOvarian cancer (OC) is one of the fatal gynecologic malignancies. However, there are no effective prognostic or therapeutic indicators for OC. Herein, we aim to reveal the potential function of targeting protein for Xklp2 (TPX2) in OC progression.MethodsImmunohistochemical and bioinformatic analyses were used to evaluate the level of TPX2 in OC samples. Effects of TPX2 on cell proliferation, cell apoptosis and ROS production were evaluated in vivo and in vitro. Mass spectrometry, Co‐IP and immunofluorescence assays were performed to identify and verify protein‐protein interactions.ResultsOur data showed that pathological overexpression (OE) of the TPX2 in OC could manifest a poor prognosis. Functional studies demonstrated that TPX2 silencing led to the suppression of cell proliferation in vitro and in vivo through an increase in reactive oxygen species (ROS) level and apoptosis, while TPX2 OE exhibited the opposite effect. Furthermore, by mass spectrometric analysis, we identified a novel interacting partner, Lamin A/C, for TPX2. Mechanistically, TPX2 regulated Lamin A/C's stability by modulating the level of phospho‐Lamin A/C (Ser 22).ConclusionOur findings thus suggest that TPX2 may be a promising therapeutic target for OC.

Targeting endoplasmic reticulum stress signaling in ovarian cancer therapy

The endoplasmic reticulum (ER), an organelle present in various eukaryotic cells, is responsible for intracellular protein synthesis, post-translational modification, and folding and transport, as well as the regulation of lipid and steroid metabolism and Ca2+ homeostasis. Hypoxia, nutrient deficiency, and a low pH tumor microenvironment lead to the accumulation of misfolded or unfolded proteins in the ER, thus activating ER stress (ERS) and the unfolded protein response, and resulting in either restoration of cellular homeostasis or cell death. ERS plays a crucial role in cancer oncogenesis, progression, and response to therapies. This article reviews current studies relating ERS to ovarian cancer, the most lethal gynecologic malignancy among women globally, and discusses pharmacological agents and possible targets for therapeutic intervention.

Clinical Value of Serum and Tissue AGR2 for Diagnosis and Prognosis in Epithelial Ovarian Cancer

TTK is a potential therapeutic target for cisplatin-resistant ovarian cancer

Abstract Background Drug resistance and recurrence are main contributors to the poor prognosis of ovarian cancer. Cisplatin is a platinum compound which is widely used in the treatment of various solid tumors including ovarian cancer. Up to now, the mechanism of cisplatin resistance in ovarian cancer is unclear. Threonine and tyrosine kinase (TTK), an integral part of the spindle assembly checkpoint, may be a potential new target associated with chemotherapy sensitivity. Results TTK was up-regulated in the cisplatin-resistant ovarian cancer cell line. Down-regulation of TTK could recover the sensitivity of cisplatin-resistant ovarian cancer cells to cisplatin treatment. Mechanistically, the PI3K/AKT signaling pathway was activated in cisplatin-resistant cells, and this pathway would be affected by TTK expression. Furthermore, TTK was highly expressed in the tissues of ovarian cancer patients, especially those acquired resistance to cisplatin. Conclusions Our study revealed that TTK may be a promising therapeutic target for cisplatin-resistant ovarian cancer.

Up-regulation of GSTT1 in serous ovarian cancer associated with resistance to TAXOL / carboplatin

AbstractSerous ovarian cancer (SOC) is the most common women cancer and the leading cause of cancer-related mortality among the gynaecological malignancies. Although effective chemotherapeutics combined with surgery are developed for the treatment, the five-year survival rate is unsatisfactory due to chemoresistance. To overcome this shortcoming of chemotherapy, we established taxol and carboplatin resistant SOC cell lines for the understandings of the molecular and cellular mechanisms of chemoresistance. Here, we found that these chemoresistant cell lines showed less viability and proliferation, due to more cells arrested at G0/G1 phase. Glutathione-S-transferases-theta1 (GSTT1) was significantly upregulated in these chemoresistant cells, along with other chemoresistant genes. Meanwhile, GSTT1 expression was also significantly upregulated in the SOC patient tissues after taxol treatment, indicating this upregulation was physiologically relevant to chemotherapy. Further, suppression of GSTT1 expression by shRNA in SOC cell lines led to more sensitivity to drug treatment, through increasing divided cells and promoting cell death. Moreover, the expression of DNA topoisomerase 1 (Topo I) was in synergy with that of GSTT1 in the chemoresistant cells, and GSTT1 can bind to Topo I in vitro, which suggested GSTT1 could function through DNA repair mechanism during chemoresistance. In summary, our data imply that GSTT1 may be a potential biomarker or indicator of drug resistance in serous ovarian cancer.