The application of the fibroblast activation protein α-targeted immunotherapy strategy.

Cancer immunotherapy has primarily been focused on attacking tumor cells. However, given the close interaction between tumor cells and cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME), CAF-targeted strategies could also contribute to an integrated cancer immunotherapy. Fibroblast activation protein α (FAP α) is not detectible in normal tissues, but is overexpressed by CAFs and is the predominant component of the stroma in most types of cancer. FAP α has both dipeptidyl peptidase and endopeptidase activities, cleaving substrates at a post-proline bond. When all FAP α-expressing cells (stromal and cancerous) are destroyed, tumors rapidly die. Furthermore, a FAP α antibody, FAP α vaccine, and modified vaccine all inhibit tumor growth and prolong survival in mouse models, suggesting FAP α is an adaptive tumor-associated antigen. This review highlights the role of FAP α in tumor development, explores the relationship between FAP α and immune suppression in the TME, and discusses FAP α as a potential immunotherapeutic target.

Inverse agonist of estrogen-related receptor α suppresses the growth of triple negative breast cancer cells through ROS generation and interaction with multiple cell signaling pathways.

There is an urgent clinical need for targeted therapy approaches for triple-negative breast cancer (TNBC) patients. Increasing evidences suggested that the expression of estrogen-related receptor alpha (ERRα) was correlate with unfavorable clinical outcomes of breast cancer patients. We here show that inhibition of ERRα by its inverse agonist XCT-790 can suppress the proliferation, decrease G2/M phases, and induce mitochondrial-related apoptosis of TNBC cells. XCT-790 elevates the proteins related to endoplasmic reticulum (ER) stress such as ATF4/6, XBT-1 and CHOP. It also increases the expression of growth inhibition related proteins such as p53 and p21. Further, XCT-790 can increase the generation of reactive oxygen species (ROS) in TNBC cells mainly through inhibition of SOD1/2. While ROS scavenger NAC abolishes XCT-790 induced ER-stress and growth arrest. XCT-790 treatment can rapidly activate the signal molecules including ERK1/2, p38-MAPK, JNK, Akt, p65, and IκBα, while NAC attenuates effects of XCT-790 induced phosphorylation of ERK1/2, p38-MAPK and Akt. Further, the inhibitors of ERK1/2, JNK, Akt, and NF-κB attenuate XCT-790 induced ROS generation. These data suggest that AKT/ROS and ERK/ROS positive feedback loops, NF-κB/ROS, and ROS/p38-MAPK, are activated in XCT-790 treated TNBC cells. In vivo experiments show that XCT-790 significantly suppresses the growth of MDA-MB-231 xenograft tumors, which is associated with up regulation of p53, p21, ER-stress related proteins while down regulation of bcl-2. The present discovery makes XCT-790 a promising candidate drug and lays the foundation for future development of ERRα-based therapies for TNBC patients.

Signals involved in the effects of bisphenol A (BPA) on proliferation and motility of Leydig cells: a comparative proteomic analysis.

Recent studies indicated that bisphenol A (BPA) can disrupt spermatogenesis and then cause male infertility. The present study revealed that BPA greater than 10-6 M inhibited the proliferation of Leydig TM3 cells via a concentration dependent manner. The proteomic study revealed that 50 proteins were modulated in TM3 cells following exposure to BPA, which was relevant to structure, motility, cell metabolism, protein and nucleotide processing, and cell proliferation. Furthermore, BPA increased the in vitro migration and invasion of Leydig TM3 cells, which might be due to the BPA's modulation of proteins related to cell structure and motility such as actin and heat shock protein (HSP). Silencing of galectin-1, which was up regulated by BPA, significantly abolished the BPA-induced migration of TM3 cells. BPA treatment obviously increased the phosphorylation of ERK1/2 and Akt, while only PD98509 (ERK1/2 inhibitor) significantly attenuated BPA induced up regulation of galectin-1. Furthermore, PD98509 also reversed BPA induced migration of TM3 cells. Our study demonstrated that xenoestrogen BPA at micromolar or greater concentrations can modulate protein profiles, inhibit cell proliferation, and promote the in vitro migration and invasion of Leydig TM3 cells. It provided new insight into the mechanisms responsible for BPA induced male infertility.

Bisphenol A modulates colorectal cancer protein profile and promotes the metastasis via induction of epithelial to mesenchymal transitions.

More and more evidences indicate that endocrine disruptor chemicals such as bisphenol A (BPA) can act as carcinogens and enhance susceptibility to tumorigenesis. Although the gut is in direct contact with orally ingested BPA, effects of BPA on occurrence and development of colorectal cancer remain an unexplored endpoint. Colorectal cancer SW480 cells treated with nanomolar (10(-8) M) or greater (10(-5) M) concentrations of BPA were compared with responses of a control group. Proteomic study revealed that more than 56 proteins were modulated following exposure to BPA, which are relevant to structure, motility and proliferation of cells, production of ATP, oxidative stress, and protein metabolism. Further studies revealed that BPA increased migration and invasion and triggered transformations from epithelial to mesenchymal transitions (EMTs) of colorectal cancer cells, which was characterized by acquiring mesenchymal spindle-like morphology and increasing the expression of N-cadherin with a concomitant decrease of E-cadherin. Accordingly, BPA treatment increased the expression of transcription factor Snail. Furthermore, signal AKT/GSK-3ß-mediated stabilization of Snail is involved during BPA-induced EMT of colon cancer cells. Our study first demonstrated that the xenoestrogen BPA at nanomolar and greater concentrations modulates the protein profiles and promotes the metastasis of colorectal cancer cells via induction of EMT.

Bisphenol A stimulates human lung cancer cell migration via upregulation of matrix metalloproteinases by GPER/EGFR/ERK1/2 signal pathway.

Lung cancer is one of the leading causes of cancer deaths worldwide. Recent evidences indicated that bisphenol A (BPA), a wide contaminant with endocrine disrupting activity, could enhance the susceptibility of carcinogenesis. Although there are increasing opportunities for lung cells exposure to BPA via inhalation, there is no study concerning the effects of BPA on the development of lung cancer. The present study revealed that BPA less than 10(-4)M had limited effects on the proliferation of lung cancer A549 cells, however, BPA treatment significantly stimulated the in vitro migration and invasion of cells combing with the morphological changes and up regulation of matrix metalloproteinase-2 (MMP-2) and MMP-9. G-protein-coupled estrogen receptor (GPER), while not estrogen receptor α/ß (ERα/ß), mediated the BPA induced up regulation of MMPs. Further, BPA treatment induced rapid activation of ERK1/2 via GPER/EGFR. GPER/ERFR/ERK1/2 mediated the BPA induced upregulation of MMPs and in vitro migration of lung cancer A549 cells. In summary, our data presented here revealed for the first time that BPA can promote the in vitro migration and invasion of lung cancer cells via upregulation of MMPs and GPER/EGFR/ERK1/2 signals, which mediated these effects. This study suggested that more attention should be paid on the BPA and other possible environmental estrogens induced development of lung cancer.

Polybrominated diphenyl ethers (PBDEs) in human samples of mother-newborn pairs in South China and their placental transfer characteristics.

There are limited data concerning the placenta transfer characteristics and accumulation of polybrominated diphenyl ethers (PBDEs) in infants. However, PBDEs received increasing health concerns due to their endocrine disrupt and neurodevelopment toxicity effects. The present study assessed the accumulation of PBDEs in 30 paired placenta, breast milk, fetal cord blood, and neonatal urine samples collected from five major cities of the South China. The age of mothers ranged from 21 to 39 (mean 27.6±4.56). The ∑PBDE concentrations were 15.8±9.88 ng g(-1) lipid in placenta, 13.2±7.64 ng g(-1) lipid in breast milk, 16.5±19.5 ng g(-1) lipid in fetal cord blood, and 1.80±1.99 ng ml(-1) in neonatal urine. BDE-47 was the predominant congener in all types of human sample. Octa-BDEs such as BDE-196/-197 were detected highly in placenta and cord blood while moderately in breast milk and neonatal urine. Significant (p<0.01) correlations were observed for both total and most individual PBDEs in cord blood-maternal placenta and breast milk-urine paired individual samples. The extent of placental transfer of higher brominated BDEs such as BDE-196/-197 was greater than that of BDE-47. The estimated daily intake (EDI) analysis for breast-fed infants revealed that newborns in these areas were exposed to relatively high levels of PBDEs via breast milk. Our study not only provided systematic fundamental data for PBDE distribution but also revealed the placenta transfer characteristics of PBDE congeners in South China.

Signaling related with biphasic effects of bisphenol A (BPA) on Sertoli cell proliferation: a comparative proteomic analysis.

BACKGROUND: Biphasic effects on cell proliferation of bisphenol A (BPA) can occur at lesser or greater exposures. Sertoli cells play a pivotal role in supporting proliferation and differentiation of germ cells. The mechanisms responsible for inverse effects of great and low concentrations of BPA on Sertoli cell proliferation need further study. METHODS: We utilized proteomic study to identify the protein expression changes of Sertoli TM4 cells treated with 10(-8)M and 10(-5)M BPA. The further mechanisms related to mitochondria, energy metabolism and oxidative stress were investigated by qRT-PCR and Western-blotting analysis. RESULTS: Proteomic studies identified 36 proteins and two major clusters of proteins including energy metabolism and oxidative stress expressed with opposite changes in Sertoli cells treated with 10(-8)M and 10(-5)M BPA, respectively, for 24h. Exposure to 10(-5)M BPA resulted in greater oxidative stress and then inhibited cell proliferation, while ROS scavenger NAC effectively blocked these effects. Exposure to 10(-8)M BPA caused higher intercellular ATP, greater activities of mitochondria, and resulted in significant proliferation of TM4 cells, while oligomycin A, an inhibitor of ATP synthase, abolished these growth advantages. CONCLUSIONS: Our study demonstrated that micromolar BPA inhibits proliferation of Sertoli cells by elevating oxidative stress while nanomolar BPA stimulates proliferation by promoting energy metabolism. GENERAL SIGNIFICANCE: Micromolar BPA inhibits cell proliferation by elevating oxidative stress while nanomolar BPA stimulates cell proliferation by promoting energy metabolism.

Involvement of activating ERK1/2 through G protein coupled receptor 30 and estrogen receptor α/ß in low doses of bisphenol A promoting growth of Sertoli TM4 cells.

Sertoli cells play a pivotal role in supporting proliferation of germ cells and differentiation during spermatogenesis in mammals. Nanomolar concentrations of Bisphenol A (BPA) can significantly stimulate the proliferation of mouse immature Sertoli (TM4) cells. However, mechanisms by which BPA caused these effects were still unclear. In the present study, an inverse U-shaped curve was observed when treating TM4 cells with increasing doses of BPA: 1 to 10nM BPA significantly stimulated the proliferation of TM4 cells and increased the proportion of cells in S phase; >1 µM BPA caused lesser proliferation of cells. Exposure of TM4 cells to G15 or ICI 182,780, which are specific antagonists of GPR30 and estrogen receptor α/ß (ERα/ß), respectively, abolished BPA-induced proliferation of cells, which suggests that both GPR30 and ERα/ß were involved in the observed effects of BPA. Furthermore, exposure to BPA caused rapid (5 min) activation of ERK1/2 via both GPR30 and ERα/ß. Blocking the GPR30/EGFR signal transduction pathway by antagonists suppressed both phosphorylation of ERK and BPA-induced cell proliferation. BPA up-regulated mRNA and protein expression of GPR30 in a concentration-dependent manner. In summary, the results reported here indicated that activating ERK1/2 through GPR30 and ERα/ß is involved in low doses of BPA that promoted growth of Sertoli TM4 cells. The GPR30/EGFR/ERK signal is the downstream transduction pathway in BPA-induced proliferation of TM4 Sertoli cells.

Histone deacetylase inhibitor induction of epithelial-mesenchymal transitions via up-regulation of Snail facilitates cancer progression.

Histone deacetylase inhibitors (HDACIs) are now emerging as a new class of anticancer drugs. Some of them have been used in clinical treatment for tumors, most impressively in the hematological tumors. But their single-agent activities in epithelial-derived tumors are limited. The mechanisms of these actions of HDACIs are not yet well understood. In this study, it was found for the first time that HDACIs were able to induce epithelial-mesenchymal transitions (EMT) which is believed to trigger tumor cell invasion and metastasis. We show that HDACIs induce fibroblast-like morphology, up-regulate Snail and Vimentin and down-regulate E-cadherin in epithelial cell-derived tumor cell lines. It demonstrates that HDACI treatment enhances further Snail acetylation and reduces its ubiquitylation, and induces Snail transcription as well as Snail nuclear translocation in CNE2 cells. Snail knockdown by siRNAs prevents the change in cell morphology and Vimentin up-regulation in response to HDACIs. The results suggested that Snail plays an important role in the HDACI-induced EMT. It is very crucial for a better understanding of clinical therapeutical failure of HDACIs in the patients with epithelial cell-derived cancers. Therefore, our results indicate that more attention should be paid to the cancer treatment using HDACIs due to the fact that it will enhance the spread risks of cancer cells to facilitate cancer progression and it is very important to select appropriate drugs for different tumors.

[Curcumin inhibiting the expression of indoleamine 2,3-dioxygenase induced by IFN-gamma in cancer cells].

OBJECTIVE: To investigate the effect of curcumin on indoleamine 2, 3 -dioxygenase (IDO) expression induced by IFN-gamma in cancer cells. METHODS: A431, HeLa, HepG2, CNE2 cells were treated with curcumin for 24 hours, then the cell proliferation was detected by methyl thiazolyl tetrazolium (MTF) assay. The effects of curcumin on IDO expression induced by IFN-gamma in these cancer cells were demonstrated by Western blot. The transcription of interferon responsive factor-1 (IRF-1), which was a key transcription factor regulating IDO expression, was analyzed by reverse transcription polymerase chain reaction (RT-PCR) under the treatment of curcumin. RESULTS: Curcumin inhibited the expression of IDO in these cancer cells. However, curcumin did not inhibit the transcription of IRF-1 in cancer cells. CONCLUSION: Curcumin could inhibit the expression of IDO in cancer cells.