In Vitro Antimetastatic Effect of Phosphatidylinositol 3-Kinase Inhibitor ZSTK474 on Prostate Cancer PC3 Cells

Jiang

Molecular Medicine Reports

et al. 2014

Girdin is an actin-binding Akt substrate that is involved in the regulation of cell migration. Accumulating evidence has revealed that girdin has regulatory effects on invasion and metastasis in several types of cancer. However, the role of girdin in esophageal squamous cell carcinomas (ESCCs) is yet to be investigated. In the present study, tissue microarray data revealed that among 95 cases of ESCC, 27 cases (28.7%) exhibited a low expression of girdin, while 67 cases (71.3%) had an enhanced expression of girdin. However, among 78 cases of adjacent tissues, 64 cases (82.1%) did not express girdin and 14 cases (17.9%) exhibited a low expression of girdin. Furthermore, the expression of girdin was significantly associated with the tumor stage, lymph node metastasis stage, and tumor, lymph node and metastasis stage. Of note, the mean survival time of girdin-positive cases was only 30.62±2.99 months, while it was 53.37±5.02 months in girdin-negative cases, indicating that girdin protein expression is an independent prognostic factor of poor survival. Talen-mediated girdin knockout (KO) significantly suppressed cellular proliferation, migration and invasion in ESCC ECA109 cells. In conclusion, the present study suggested that girdin protein expression was significantly correlated with cancer progression and poor prognosis in ESCCs, and that girdin had a positive role in the regulation of cell proliferation, migration and invasion in ESCC cells. Therefore, girdin may be a potential candidate for the development of novel prognostic tools and therapeutic strategies for ESCCs.

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 98%

Talen-mediated girdin knockout downregulates cell proliferation, migration and invasion in human esophageal carcinoma ECA109 cells

Jiang

Molecular Medicine Reports

et al. 2014

Acta Pharmaceutica Sinica B

“…In addition, hypoxia-inducible factor 1 α (HIF-1 α ) was reported to be up-regulated downstream of mTORC1, and therefore promotes tumor angiogenesis by transcribing vascular endothelial growth factor (VEGF) 33 . By activating NF- κ B and inducing secretion of matrix metalloproteinase (MMP), Akt also promotes cell invasion 34 . However, phosphorylation of S6K negatively regulates insulin receptor substrate (IRS), leading to a negative feedback loop35, 36, 37.…”

Section: Pi3k Critical Element That Is Involved In Carcinogenesismentioning

confidence: 99%

“…The in vivo anti-angiogenic effect was attributed to its dual inhibition mechanism: inhibition of VEGF secretion in cancer cells and direct inhibition of PI3K in endothelial cells 96 . In addition, ZSTK474 inhibited migration and invasion of prostate cancer cell PC3, and blocked the phosphorylation of Girdin and production of MMPs, suggesting the anti-metastatic activity 34 . Like other novel PI3K inhibitors such as NVP-BEZ235, BKM120 and GDC-0941, ZSTK474 inhibits both mutant PIK3CA and the wild type one 56 .…”

Section: Pi3k Inhibitors Approved or In Clinical Trialsmentioning

confidence: 99%

Class I phosphatidylinositol 3-kinase inhibitors for cancer therapy

Wenyuan

Qiu

Kong

2017

Self Cite

128

The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in human cancers. Class I PI3Ks are lipid kinases that phosphorylate phosphatidylinositol 4,5-bisphosphate (PIP2) at the 3-OH of the inositol ring to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3), which in turn activates Akt and the downstream effectors like mammalian target of rapamycin (mTOR) to play key roles in carcinogenesis. Therefore, PI3K has become an important anticancer drug target, and currently there is very high interest in the pharmaceutical development of PI3K inhibitors. Idelalisib has been approved in USA and Europe as the first-in-class PI3K inhibitor for cancer therapy. Dozens of other PI3K inhibitors including BKM120 and ZSTK474 are being evaluated in clinical trials. Multifaceted studies on these PI3K inhibitors are being performed, such as single and combinational efficacy, resistance, biomarkers, etc. This review provides an introduction to PI3K and summarizes key advances in the development of PI3K inhibitors.

“…In particular, idelalisib (CAL101) has become the first approved PI3K inhibitor for treatment of patients with relapsed chronic lymphocytic leukemia (17). We previously reported that the pan-PI3K inhibitor ZSTK474 exhibited antimetastatic effects via blocking migration and suppressing matrix metalloproteinase secretion of prostate cancer PC3 cells (18). However, there is little information about the role that each individual PI3K isoform plays in cancer cell migration.…”

mentioning

confidence: 99%

Phosphatidylinositol 3‐kinase β and β isoforms play key roles in metastasis of prostate cancer DU145 cells

et al. 2018

Self Cite

Metastasis is the main cause of the lethality of prostate cancer. Class I phosphatidylinositol 3‐kinases (PI3Ks), which contain 4 isoforms, α, β, δ, and γ, are known to play important roles in cell growth, migration, invasion, and so on. However, the respective role of each PI3K isoform in cancer cell migration and invasion remains unknown. In a study that aimed to elucidate the respective role of the 4 PI3K isoforms, we investigated the change in migratory and invasive ability of DU145 cells after treatment with each PI3K isoform‐specific inhibitor. Both migration and invasion of DU145 cells were potently blocked by each of the PI3Kβ inhibitors (GSK2636771 and TGX221) and PI3Kδ inhibitors (CAL101 and IC87114) while not obviously affected by PI3Kα inhibitor BYL719 or PI3Kγ inhibitor AS252424. Furthermore, knocking down PI3Kβ or PI3Kδ isoform led to a significant decrease in migration of DU145. The results suggest that PI3Kβ and PI3Kδ play key roles in prostate cancer cell migration, while PI3Kα and PI3Kγ might be redundant. Oral administration of GSK2636771 (100 mg/kg) and CAL101 (30 mg/kg) inhibited tumor growth in bone, an experimental model by intratibia injection of DU145 cells, with improved bone structure and bone mineral density analyzed by micro‐computed tomography. Tissue staining indicated reduction of metastatic DU145 cells and osteoclasts in the bones of GSK2636771‐ and CAL101‐treated mice compared to the untreated group. In summary, our results indicated the distinct roles of 4 PI3K isoforms in the migration of prostate cancer DU145 cells, and they demonstrated the in vitro and in vivo antimetastatic effect of PI3K‐isoform specific inhibitors, most of which are in clinical trials.—Zhang, Z., Liu, J., Wang, Y., Tan, X., Zhao, W., Xing, X., Qiu, Y., Wang, R., Jin, M., Fan, G., Zhang, P., Zhong, Y., Kong, D. Phosphatidylinositol 3‐kinase β and δ isoforms play key roles in metastasis of prostate cancer DU145 cells. FASEB J. 32, 5967–5975 (2018). http://www.fasebj.org