Glyoxalase-1-Dependent Methylglyoxal Depletion Sustains PD-L1 Expression in Metastatic Prostate Cancer Cells: A Novel Mechanism in Cancer Immunosurveillance Escape and a Potential Novel Target to Overcome PD-L1 Blockade Resistance

Metastatic prostate cancer (mPCa) is a disease for which to date there is not curative therapy. Even the recent and attractive immunotherapeutic approaches targeting PD-L1, an immune checkpoint protein which helps cancer cells to escape from immunosurveillance, have proved ineffective. A better understanding of the molecular mechanisms contributing to keep an immunosuppressive microenvironment associated with tumor progression and refractoriness to PD-L1 inhibitors is urgently needed. In the present study, by using gene silencing and specific activators or scavengers, we demonstrated, in mPCa cell models, that methylglyoxal (MG), a potent precursor of advanced glycation end products (AGEs), especially 5-hydro-5-methylimidazolone (MG-H1), and its metabolizing enzyme, glyoxalase 1 (Glo1), contribute to maintain an immunosuppressive microenvironment through MG-H1-mediated PD-L1 up-regulation and to promote cancer progression. Moreover, our findings suggest that this novel mechanism might be responsible, at least in part, of mPCa resistance to PD-L1 inhibitors, such as atezolizumab, and that targeting it may sensitize cells to this PD-L1 inhibitor. These findings provide novel insights into the mechanisms of mPCa immunosurveillance escape and help in providing the basis to foster in vivo research toward novel therapeutic strategies for immunotherapy of mPCa.

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Tumor- and osteoclast-derived NRP2 in prostate cancer bone metastases

Bone Research ◽

10.1038/s41413-021-00136-2 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Navatha Shree Polavaram ◽

Samikshan Dutta ◽

Ridwan Islam ◽

Arup K. Bag ◽

Sohini Roy ◽

...

Keyword(s):

Prostate Cancer ◽

Bone Metastasis ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Osteoclast Differentiation ◽

Potential Effect ◽

Tumor Burden ◽

Bone Lesions ◽

Prostate Cancer Cells

AbstractUnderstanding the role of neuropilin 2 (NRP2) in prostate cancer cells as well as in the bone microenvironment is pivotal in the development of an effective targeted therapy for the treatment of prostate cancer bone metastasis. We observed a significant upregulation of NRP2 in prostate cancer cells metastasized to bone. Here, we report that targeting NRP2 in cancer cells can enhance taxane-based chemotherapy with a better therapeutic outcome in bone metastasis, implicating NRP2 as a promising therapeutic target. Since, osteoclasts present in the tumor microenvironment express NRP2, we have investigated the potential effect of targeting NRP2 in osteoclasts. Our results revealed NRP2 negatively regulates osteoclast differentiation and function in the presence of prostate cancer cells that promotes mixed bone lesions. Our study further delineated the molecular mechanisms by which NRP2 regulates osteoclast function. Interestingly, depletion of NRP2 in osteoclasts in vivo showed a decrease in the overall prostate tumor burden in the bone. These results therefore indicate that targeting NRP2 in prostate cancer cells as well as in the osteoclastic compartment can be beneficial in the treatment of prostate cancer bone metastasis.

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miR-125b Suppresses Proliferation and Invasion by Targeting MCL1 in Gastric Cancer

BioMed Research International ◽

10.1155/2015/365273 ◽

2015 ◽

Vol 2015 ◽

pp. 1-10 ◽

Cited By ~ 19

Author(s):

Shihua Wu ◽

Feng Liu ◽

Liming Xie ◽

Yaling Peng ◽

Xiaoyuan Lv ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Therapeutic Potential ◽

Clinical Stage ◽

Gastric Cancer Cells ◽

Gastric Cancer Progression

Understanding the molecular mechanisms underlying gastric cancer progression contributes to the development of novel targeted therapies. In this study, we found that the expression levels of miR-125b were strongly downregulated in gastric cancer and associated with clinical stage and the presence of lymph node metastases. Additionally, miR-125b could independently predict OS and DFS in gastric cancer. We further found that upregulation of miR-125b inhibited the proliferation and metastasis of gastric cancer cells in vitro and in vivo. miR-125b elicits these responses by directly targeting MCL1 (myeloid cell leukemia 1), which results in a marked reduction in MCL1 expression. Transfection of miR-125b sensitizes gastric cancer cells to 5-FU-induced apoptosis. By understanding the function and molecular mechanisms of miR-125b in gastric cancer, we may learn that miR-125b has the therapeutic potential to suppress gastric cancer progression and increase drug sensitivity to gastric cancer.

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miR-26a regulates extracellular vesicle secretion from prostate cancer cells via targeting SHC4, PFDN4 and CHORDC1

10.1101/646380 ◽

2019 ◽

Author(s):

Fumihiko Urabe ◽

Nobuyoshi Kosaka ◽

Yurika Sawa ◽

Tomofumi Yamamoto ◽

Yusuke Yamamoto ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Extracellular Vesicle ◽

Suppressive Effect ◽

Prostate Cancer Cells ◽

Detailed Mechanism ◽

Novel Strategy ◽

Vesicle Secretion

AbstractExtracellular vesicles (EVs) are known to be involved in intercellular communication during cancer progression; thus, elucidating the detailed mechanism will contribute to the development of a novel strategy for EV-targeted cancer treatment. However, the biogenesis of EVs in cancer cells is not completely understood. MicroRNAs (miRNAs) regulate a variety of physiological and pathological phenomena; thus, miRNAs could regulate EV secretion. Here, we performed high-throughput miRNA-based screening to identify the regulators of EV secretion using an ExoScreen assay. By using this miRNA-based screening, we identified miR-26a, which was reported as a tumor suppressive miRNA, as a miRNA involved in EV secretion from prostate cancer (PCa) cells. In addition, we found that the SHC4, PFDN4, and CHORDC1 genes regulate EV secretion in PCa cells. Suppression of these genes by siRNAs significantly inhibited the secretion of EVs in PCa cells. Furthermore, the progression of PCa cells was inhibited in an in vivo study. On the other hand, injection of EVs isolated from PCa cells partially rescued this suppressive effect on tumor growth. Taken together, our findings suggest that miR-26a regulates EV secretion via targeting SHC4, PFDN4, and CHORDC1 in PCa cells, resulting in the suppression of PCa progression.

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miR-26a regulates extracellular vesicle secretion from prostate cancer cells via targeting SHC4, PFDN4, and CHORDC1

Science Advances ◽

10.1126/sciadv.aay3051 ◽

2020 ◽

Vol 6 (18) ◽

pp. eaay3051 ◽

Cited By ~ 4

Author(s):

Fumihiko Urabe ◽

Nobuyoshi Kosaka ◽

Yurika Sawa ◽

Yusuke Yamamoto ◽

Kagenori Ito ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

High Throughput ◽

Intercellular Communication ◽

Extracellular Vesicle ◽

Prostate Cancer Cells ◽

Biological Phenomena ◽

Vesicle Secretion

Extracellular vesicles (EVs) are involved in intercellular communication during cancer progression; thus, elucidating the mechanism of EV secretion in cancer cells will contribute to the development of an EV-targeted cancer treatment. However, the biogenesis of EVs in cancer cells is not fully understood. MicroRNAs (miRNAs) regulate a variety of biological phenomena; thus, miRNAs could regulate EV secretion. Here, we performed high-throughput miRNA-based screening to identify the regulators of EV secretion using an ExoScreen assay. By using this method, we identified miR-26a involved in EV secretion from prostate cancer (PCa) cells. In addition, we found that SHC4, PFDN4, and CHORDC1 genes regulate EV secretion in PCa cells. Furthermore, the progression of the PCa cells suppressing these genes was inhibited in an in vivo study. Together, our findings suggest that miR-26a regulates EV secretion via targeting SHC4, PFDN4, and CHORDC1 in PCa cells, resulting in the suppression of PCa progression.

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MicroRNA-374b inhibits breast cancer progression through regulating CCND1 and TGFA genes

Carcinogenesis ◽

10.1093/carcin/bgab005 ◽

2021 ◽

Author(s):

Yan Liu ◽

Ai Zhang ◽

Ping-Ping Bao ◽

Li Lin ◽

Yina Wang ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Breast Cancer Cells ◽

Molecular Mechanisms ◽

Breast Cancer Progression ◽

Breast Cancer Cell Lines ◽

Malignant Behavior

Abstract Emerging evidence indicates that microRNAs (miRNAs) play a critical role in breast cancer development. We recently reported that a higher expression of miR-374b in tumor tissues was associated with a better disease-free survival of triple-negative breast cancer (TNBC). However, the functional significance and molecular mechanisms underlying the role of miR-374b in breast cancer are largely unknown. In this current study, we evaluated the biological functions and potential mechanisms of miR-374b in both TNBC and non-TNBC. We found that miR-374b was significantly downregulated in breast cancer tissues, compared to adjacent tissues. MiR-374b levels were also lower in breast cancer cell lines, as compared to breast epithelial cells. In vitro and in vivo studies demonstrated that miR-374b modulates the malignant behavior of breast cancer cells, such as cell proliferation in 2D and 3D, cell invasion ability, colony forming ability, and tumor growth in mice. By using bioinformatics tools, we predicted that miR-374b plays a role in breast cancer cells through negatively regulating cyclin D1 (CCND1) and transforming growth factor alpha (TGFA). We further confirmed that CCND1 and TGFA contribute to the malignant behavior of breast cancer cells in vitro and in vivo. Our rescue experiments showed that overexpressing CCND1 or TGFA reverses the phenotypes caused by miR-374b overexpression. Taken together, our studies suggest that miR-374b modulates malignant behavior of breast cancer cells by negatively regulating CCND1 and TGFA genes. The newly identified miR-374b-mediated CCND1 and TGFA gene silencing may facilitate a better understanding of the molecular mechanisms of breast cancer progression.

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Inhibition of Autophagy Promotes Hemistepsin A-Induced Apoptosis via Reactive Oxygen Species-Mediated AMPK-Dependent Signaling in Human Prostate Cancer Cells

Biomolecules ◽

10.3390/biom11121806 ◽

2021 ◽

Vol 11 (12) ◽

pp. 1806

Author(s):

Kwang-Youn Kim ◽

Un-Jung Yun ◽

Seung-Hee Yeom ◽

Sang-Chan Kim ◽

Hu-Jang Lee ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Xenograft Model ◽

Underlying Mechanism ◽

Ros Generation ◽

Prostate Cancer Cells ◽

Ros Scavenger ◽

Induced Apoptosis

Chemotherapy is an essential strategy for cancer treatment. On the other hand, consistent exposure to chemotherapeutic drugs induces chemo-resistance in cancer cells through a variety of mechanisms. Therefore, it is important to develop a new drug inhibiting chemo-resistance. Although hemistepsin A (HsA) is known to have anti-tumor effects, the molecular mechanisms of HsA-mediated cell death are unclear. Accordingly, this study examined whether HsA could induce apoptosis in aggressive prostate cancer cells, along with its underlying mechanism. Using HsA on two prostate cancer cell lines, PC-3 and LNCaP cells, the cell analysis and in vivo xenograft model were assayed. In this study, HsA induced apoptosis and autophagy in PC-3 cells. HsA-mediated ROS production attenuated HsA-induced apoptosis and autophagy after treatment with N-acetyl-L-cysteine (NAC), a ROS scavenger. Moreover, autophagy inhibition by 3-MA or CQ is involved in accelerating the apoptosis induced by HsA. Furthermore, we showed the anti-tumor effects of HsA in mice, as assessed by the reduced growth of the xenografted tumors. In conclusion, HsA induced apoptosis and ROS generation, which were blocked by protective autophagy signaling.

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Platelet Microparticles Increase Pro-Angiogenic Properties of Prostate Cancer Cell Lines

Blood ◽

10.1182/blood.v118.21.1147.1147 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1147-1147 ◽

Cited By ~ 1

Author(s):

Olga Dashevsky ◽

Ela Shai ◽

David Varon

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Conflicts Of Interest ◽

Gelatin Zymography ◽

High Rate ◽

Lipid Mediator ◽

Prostate Cancer Cells ◽

Platelet Microparticles

Abstract Abstract 1147 Platelets are key players in hemostasis, but are also involved in fundamental processes of vascular biology as angiogenesis, tissue regeneration and tumor metastasis. Platelet Microparticles (PMP) are vesicular membrane fragments shed from activated platelets, containing the platelet cytoplasmic content with a typical platelet membrane. Prostate cancer is the most frequently diagnosed noncutaneous cancer in men in western countries. A major factor of the life-threatening course of this disease is the high rate of metastasis. Circulating tumor cells encounter platelets and may activate them, resulting in a production of microparticles. We have previously reported a pro angiogenic effect of PMP, both in vitro and in vivo. We also demonstrated that prostate cancer cells that were pre-incubated with PMP acquired invasive properties. This was shown by rapid and transient increase of MMP-2 mRNA level and increased secretion of metalloproteinase-2 (MMP-2) as demonstrated by gelatin zymography. In the present study, in vivo experiments of injection of prostate cancer cells pre-incubated with PMP to the mouse tail vain showed more rapid localization of cancer cells to the lungs, compared to untreated cancer cells. Microarray assay of prostate cancer cells pre-incubated with PMP has revealed significant differences in transcriptional regulation of genes related to cell growth, survival, tumorigenicity, invasiveness, and angiogenesis that suggested a more aggressive feature of the cells. We then investigated effect of PMP on release of the pro-angiogenic cytokine IL-8 from prostate cancer cells. RT-PCR demonstrated that protein release was accompanied by increase of IL-8mRNA and changes in regulation of related transcription factors. We have shown the involvement of the signaling molecules PI3, p38 and ERK in synthesis and expression of IL-8 from prostate cancer cells and revealed the contribution of the platelet-derived lipid mediator sphingosine 1-phosphate (S1P) and angiopoietin 1 (Ang-1) to the process. Better understanding of the role of PMP in cancer development and identification of the mechanisms responsible for prostate cancer progression and aggression by the tumor microenvironment may lead to the development of novel effective therapies for metastatic disease. Disclosures: No relevant conflicts of interest to declare.

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Chinese Herbal Medicine Ganoderma tsugae Displays Potential Anti-Cancer Efficacy on Metastatic Prostate Cancer Cells

International Journal of Molecular Sciences ◽

10.3390/ijms20184418 ◽

2019 ◽

Vol 20 (18) ◽

pp. 4418 ◽

Cited By ~ 1

Author(s):

Wen-Chin Huang ◽

Meng-Shiun Chang ◽

Shih-Yin Huang ◽

Ching-Ju Tsai ◽

Pin-Hung Kuo ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Growth ◽

Cancer Progression ◽

Metastatic Prostate Cancer ◽

Xenograft Model ◽

Ethanol Extract ◽

Cancer Cell Growth ◽

Medicine Quality

Resistance to the current therapies is the main clinical challenge in the treatment of lethal metastatic prostate cancer (mPCa). Developing novel therapeutic approaches with effective regimes and minimal side effects for this fatal disease remain a priority in prostate cancer study. In the present study, we demonstrated that a traditional Chinese medicine, quality-assured Ganoderma tsugae ethanol extract (GTEE), significantly suppressed cell growth and metastatic capability and caused cell cycle arrest through decreasing expression of cyclins in mPCa cells, PC-3 and DU145 cells. GTEE also induced caspase-dependent apoptosis in mPCa cells. We further showed the potent therapeutic efficacy of GTEE by inhibiting subcutaneous PC-3 tumor growth in a xenograft model. The in vitro and in vivo efficacies on mPCa cells were due to blockade of the PI3K/Akt and MAPK/ERK signaling pathways associated with cancer cell growth, survival and apoptosis. These preclinical data provide the molecular basis for a new potential therapeutic approach toward the treatment of lethal prostate cancer progression.

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Long noncoding RNA LINC00261 suppresses prostate cancer tumorigenesis through upregulation of GATA6-mediated DKK3

Cancer Cell International ◽

10.1186/s12935-020-01484-5 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Yang Li ◽

Hai Li ◽

Xin Wei

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Prostate Cancer Progression ◽

Aberrant Expression

Abstract Background Prostate cancer is one of the leading causes of cancer death in males. Recent studies have reported aberrant expression of lncRNAs in prostate cancer. This study explores the role of LINC00261 in prostate cancer progression. Methods The differentially expressed genes, transcription factors, and lncRNAs related to prostate cancer were predicted by bioinformatics analysis. Prostate cancer tissue samples and cell lines were collected for the determination of the expression of LINC00261 by reverse transcription quantitative polymerase chain reaction. The binding capacity of LINC00261 to the transcription factor GATA6 was detected by RIP, and GATA6 binding to the DKK3 promoter region was assessed by ChIP. In addition, luciferase reporter system was used to verify whether LINC00261 was present at the DKK3 promoter. After gain- and loss-of function approaches, the effect of LINC00261 on prostate cancer in vitro and in vivo was assessed by the determination of cell proliferation, invasion and migration as well as angiogenesis. Results LINC00261, GATA6, and DKK3 were poorly expressed in prostate cancer. LINC00261 could inhibit transcriptional expression of DKK3 by recruiting GATA6. Overexpression of LINC00261 inhibited prostate cancer cells proliferation, migration, and invasion as well as angiogenesis, which could be reversed by silencing DKK3. Furthermore, LINC00261 could also suppress the tumorigenicity of cancer cells in vivo. Conclusions Our study demonstrates the inhibitory role of LINC00261 in prostate cancer progression, providing a novel biomarker for early detection of prostate cancer.

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Functional screen identifies kinases driving prostate cancer visceral and bone metastasis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1521674112 ◽

2015 ◽

Vol 113 (2) ◽

pp. E172-E181 ◽

Cited By ~ 22

Author(s):

Claire M. Faltermeier ◽

Justin M. Drake ◽

Peter M. Clark ◽

Bryan A. Smith ◽

Yang Zong ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Progression ◽

Metastatic Prostate Cancer ◽

Tissue Microarrays ◽

Functional Evaluation ◽

Castration Resistant Prostate Cancer ◽

Wild Type ◽

Prostate Cells ◽

In Vivo Screen

Mutationally activated kinases play an important role in the progression and metastasis of many cancers. Despite numerous oncogenic alterations implicated in metastatic prostate cancer, mutations of kinases are rare. Several lines of evidence suggest that nonmutated kinases and their pathways are involved in prostate cancer progression, but few kinases have been mechanistically linked to metastasis. Using a mass spectrometry-based phosphoproteomics dataset in concert with gene expression analysis, we selected over 100 kinases potentially implicated in human metastatic prostate cancer for functional evaluation. A primary in vivo screen based on overexpression of candidate kinases in murine prostate cells identified 20 wild-type kinases that promote metastasis. We queried these 20 kinases in a secondary in vivo screen using human prostate cells. Strikingly, all three RAF family members, MERTK, and NTRK2 drove the formation of bone and visceral metastasis confirmed by positron-emission tomography combined with computed tomography imaging and histology. Immunohistochemistry of tissue microarrays indicated that these kinases are highly expressed in human metastatic castration-resistant prostate cancer tissues. Our functional studies reveal the strong capability of select wild-type protein kinases to drive critical steps of the metastatic cascade, and implicate these kinases in possible therapeutic intervention.

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