scholarly journals Anticancer efficacy of monotherapy with antibodies to SIRPα/SIRPβ1 mediated by induction of antitumorigenic macrophages

2021 ◽  
Vol 119 (1) ◽  
pp. e2109923118
Author(s):  
Mariko Sakamoto ◽  
Yoji Murata ◽  
Daisuke Tanaka ◽  
Yuka Kakuchi ◽  
Takeshi Okamoto ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Cancer Cells ◽  
Cancer Immunotherapy ◽  
Tumor Targeting ◽  
Mammary Cancer ◽  
Regulatory Protein ◽  
Inhibitory Effect ◽  
Tumor Formation ◽  
Anticancer Efficacy ◽  
Killing Activity

The interaction of signal regulatory protein α (SIRPα) on macrophages with CD47 on cancer cells is thought to prevent antibody (Ab)-dependent cellular phagocytosis (ADCP) of the latter cells by the former. Blockade of the CD47-SIRPα interaction by Abs to CD47 or to SIRPα, in combination with tumor-targeting Abs such as rituximab, thus inhibits tumor formation by promoting macrophage-mediated ADCP of cancer cells. Here we show that monotherapy with a monoclonal Ab (mAb) to SIRPα that also recognizes SIRPβ1 inhibited tumor formation by bladder and mammary cancer cells in mice, with this inhibitory effect being largely dependent on macrophages. The mAb to SIRPα promoted polarization of tumor-infiltrating macrophages toward an antitumorigenic phenotype, resulting in the killing and phagocytosis of cancer cells by the macrophages. Ablation of SIRPα in mice did not prevent the inhibitory effect of the anti-SIRPα mAb on tumor formation or its promotion of the cancer cell–killing activity of macrophages, however. Moreover, knockdown of SIRPβ1 in macrophages attenuated the stimulatory effect of the anti-SIRPα mAb on the killing of cancer cells, whereas an mAb specific for SIRPβ1 mimicked the effect of the anti-SIRPα mAb. Our results thus suggest that monotherapy with Abs to SIRPα/SIRPβ1 induces antitumorigenic macrophages and thereby inhibits tumor growth and that SIRPβ1 is a potential target for cancer immunotherapy.

scholarly journals Overexpression of protein regulator of cytokinesis 1 facilitates tumor growth and indicates unfavorable prognosis of patients with colon cancer

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Tianxiang Xu ◽  
Xiaoxia Wang ◽  
Xiangdong Jia ◽  
Weishi Gao ◽  
Junhua Li ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Colon Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Cell Lines ◽  
Clinicopathological Characteristics ◽  
Tumor Formation ◽  
Down Regulation ◽  
Cancer Tissues

Abstract Background Protein regulator of cytokinesis 1 (PRC1) has been reported to play important role in the pathogenesis of various cancers. However, its role in colon cancer has not been studied. Here, we aimed to investigate the biological functions and potential mechanism of PRC1 in colon cancer. Methods The expression level of PRC1 in colon cancer tissues and cell lines was detected by quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, and immunohistochemical (IHC) staining of a tissue microarray (TMA). Furthermore, colon cancer cell lines HCT116 and SW480 were treated with short hairpin RNAs against PRC1. The biological function of PRC1 was determined by MTT proliferation, colony formation assay, cell cycle, and apoptosis assays. Then, an in vivo tumor formation assay was conducted to explore the effects of PRC1 on tumor growth. Results The mRNA and protein expression levels of PRC1 were highly expressed in colon cancer tissues and cell lines. PRC1 expression was associated with clinicopathological characteristics and overall survival of patients with colon cancer. Knockdown of PRC1 could decrease proliferation and colony forming ability of colon cancer cells, as well as arrested more cells at G2/M phase and promoted cell apoptosis. In cancer cells, the expression pattern of protein regulators included in cell cycle and apoptosis progress were reverted by PRC1 down-regulation. Additionally, PRC1 down-regulation could suppress colon tumor growth and differentiation. Conclusions We confirmed that PRC1 was overexpressed in colon cancer and was associated with poor prognosis of colon cancer patients. PRC1 down-regulation could arrest cell cycle at G2/M stage, inhibit proliferation, and elicit apoptosis. These findings showed the potential of PRC1 to be used for therapeutic approaches in colon cancer.

scholarly journals Ovariectomy is associated with metabolic impairments and enhanced mammary tumor growth in MKR mice

2015 ◽  
Vol 227 (3) ◽  
pp. 143-151 ◽  
Author(s):  
Sarit Ben-Shmuel ◽  
Eyal J Scheinman ◽  
Rola Rashed ◽  
Zila Shen Orr ◽  
Emily J Gallagher ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Blood Glucose ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Mammary Tumor ◽  
Mammary Cancer ◽  
Female Mice ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Mammary Tumor Growth

Obesity and type 2 diabetes (T2D) are associated with an increased risk of breast cancer incidence and mortality. Common features of obesity and T2D are insulin resistance and hyperinsulinemia. A mammary tumor promoting effect of insulin resistance and hyperinsulinemia was demonstrated in the transgenic female MKR mouse model of pre-diabetes inoculated with mammary cancer cells. Interestingly, in MKR mice, as well as in other diabetic mouse models, males exhibit severe hyperglycemia, while females display insulin resistance and hyperinsulinemia with only a mild increase in blood glucose levels. This gender-specific protection from hyperglycemia may be attributed to estradiol, a key player in the regulation of the metabolic state, including obesity, glucose homeostasis, insulin resistance, and lipid profile. The aim of this study was to investigate the effects of ovariectomy (including the removal of endogenous estradiol) on the metabolic state of MKR female mice and subsequently on the growth of Mvt-1 mammary cancer cells, inoculated into the mammary fat pad of ovariectomized mice, compared with sham-operated mice. The results showed an increase in body weight, accompanied by increased fat mass, elevated blood glucose levels, and hypercholesterolemia, in ovariectomized MKR mice. In addition, mammary tumor growth was significantly higher in these mice. The results suggest that ovarian hormone deficiency may promote impaired metabolic homeostasis in the hyperinsulinemic MKR female mice, which in turn is associated with an increased growth of mammary tumors.

scholarly journals eEF2 kinase enhances the expression of PD-L1 by promoting the translation of its mRNA

2020 ◽  
Author(s):  
Yu Wu ◽  
Jianling Xie ◽  
Xin Jin ◽  
Roman V. Lenchine ◽  
Xuemin Wang ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Cell Biology ◽  
Checkpoint Inhibitors ◽  
Inhibitory Effect ◽  
Upstream Open Reading Frame ◽  
Coding Region ◽  
Reading Frame ◽  
L1 Protein

AbstractEmerging advances in cancer therapy have transformed the landscape from conventional therapies towards cancer immunotherapy regimens. Recent discoveries have resulted in the development of clinical immune checkpoint inhibitors that are ‘game-changers’ for cancer immunotherapy. Here we show that eEF2K, an atypical protein kinase that inhibits the elongation stage of protein synthesis, actually promotes the synthesis of PD-L1, an immune checkpoint protein which helps cancer cells to escape from immunosurveillance. Ablation of eEF2K in prostate and lung cancer cells markedly reduced the expression levels of the PD-L1 protein. We show that eEF2K promotes the association of PD-L1 mRNAs with translationally active polyribosomes and that translation of the PD-L1 mRNA is regulated by a uORF (upstream open reading-frame) within its 5’-UTR (5’-untranslated region) which starts with a non-canonical CUG codon. This inhibitory effect is attenuated by eEF2K thereby allowing higher levels of translation of the PD-L1 coding region and enhanced expression of the PD-L1 protein. Moreover, eEF2K-depleted cancer cells are more vulnerable to immune attack by natural killer cells. Therefore, control of translation elongation can modulate the translation of this specific mRNA, one which contains an uORF that starts with CUG, and perhaps others that contain a similar feature. Taken together, our data reveal that eEF2K regulates PD-L1 expression at the level of the translation of its mRNA by virtue of a uORF in its 5’-region. This, and other roles of eEF2K in cancer cell biology (e.g., in cell survival and migration), may be exploited for the design of future therapeutic strategies.

Inhibition of Intercellular Communication between Prostate Cancer Cells by A Specific Anti-STEAP-1 Single Chain Antibody

2019 ◽  
Vol 18 (12) ◽  
pp. 1674-1679 ◽  
Author(s):  
Seyed-Alireza Esmaeili ◽  
Foroogh Nejatollahi ◽  
Amirhossein Sahebkar
Keyword(s):  
Prostate Cancer ◽  
Gap Junctions ◽  
Cancer Cells ◽  
Cancer Immunotherapy ◽  
Intercellular Communication ◽  
Lncap Cell ◽  
Inhibitory Effect ◽  
Scfv Antibody ◽  
Prostate Cancer Cells ◽  
Single Chain

Background: Six-Transmembrane epithelial antigen of the prostate-1 (STEAP-1) is present at the intercellular junctions of the secretory epithelium of prostate and is overexpressed in all steps of prostate cancer. STEAP-1 acts as a transporter protein or a putative channel between cancer cells while it has limited expression in normal human tissues. This protein has been suggested as an attractive target for prostate cancer immunotherapy. Objective: This study aimed at the development of a specific single chain fragment variable (scFv) antibody against STEAP-1 epitope and testing the inhibitory effect of the selected scFv antibody in blocking gap junctions between tumor cells. Method: In the current study, a phage library was used and a specific scFv antibody was isolated against STEAP-1 epitope using panning process. Results: PCR and DNA fingerprinting of the obtained clones demonstrated a dominant pattern of a specific clone. Binding of the selected scFv to the corresponding target on PC3 and LNCaP cell lines was tested using ELISA and flow cytometry techniques. The inhibitory effect of the selected scFv antibody in blocking gap junctions between the cells was tested using intercellular communication assay. The selected antibody reacted with the corresponding epitope in ELISA and bound to prostate cancer cells with an intensity of 44.6% (PC3 cells) and 73.4% (LNCap cells) as shown by FACS analysis. Intercellular communication assay indicated that dye transfer between the cells in PC3 and LNCaP cell lines treated with 1000 scFv/cell was significantly inhibited (80-90%). Conclusion: Our results suggested that the selected specific anti-STEAP1 scFv highly inhibited intercellular communication between prostate cancer cells and has the potential to be used as a new effective agent in prostate cancer immunotherapy.

scholarly journals Phosphorylation of DEPDC5, a component of the GATOR1 complex, releases inhibition of mTORC1 and promotes tumor growth

2019 ◽  
Vol 116 (41) ◽  
pp. 20505-20510 ◽  
Author(s):  
Sathish K. R. Padi ◽  
Neha Singh ◽  
Jeremiah J. Bearss ◽  
Virginie Olive ◽  
Jin H. Song ◽  
...  
Keyword(s):  
Amino Acid ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Regulatory Protein ◽  
Mammalian Target Of Rapamycin ◽  
Animal Experiments ◽  
Amino Acid Starvation ◽  
Inhibitory Protein

The Pim and AKT serine/threonine protein kinases are implicated as drivers of cancer. Their regulation of tumor growth is closely tied to the ability of these enzymes to mainly stimulate protein synthesis by activating mTORC1 (mammalian target of rapamycin complex 1) signaling, although the exact mechanism is not completely understood. mTORC1 activity is normally suppressed by amino acid starvation through a cascade of multiple regulatory protein complexes, e.g., GATOR1, GATOR2, and KICSTOR, that reduce the activity of Rag GTPases. Bioinformatic analysis revealed that DEPDC5 (DEP domain containing protein 5), a component of GATOR1 complex, contains Pim and AKT protein kinase phosphorylation consensus sequences. DEPDC5 phosphorylation by Pim and AKT kinases was confirmed in cancer cells through the use of phospho-specific antibodies and transfection of phospho-inactive DEPDC5 mutants. Consistent with these findings, during amino acid starvation the elevated expression of Pim1 overcame the amino acid inhibitory protein cascade and activated mTORC1. In contrast, the knockout of DEPDC5 partially blocked the ability of small molecule inhibitors against Pim and AKT kinases both singly and in combination to suppress tumor growth and mTORC1 activity in vitro and in vivo. In animal experiments knocking in a glutamic acid (S1530E) in DEPDC5, a phospho mimic, in tumor cells induced a significant level of resistance to Pim and the combination of Pim and AKT inhibitors. Our results indicate a phosphorylation-dependent regulatory mechanism targeting DEPDC5 through which Pim1 and AKT act as upstream effectors of mTORC1 to facilitate proliferation and survival of cancer cells.

scholarly journals eEF2K enhances expression of PD-L1 by promoting the translation of its mRNA

2020 ◽  
Vol 477 (22) ◽  
pp. 4367-4381
Author(s):  
Yu Wu ◽  
Jianling Xie ◽  
Xin Jin ◽  
Roman V. Lenchine ◽  
Xuemin Wang ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Cell Biology ◽  
Checkpoint Inhibitors ◽  
Inhibitory Effect ◽  
Upstream Open Reading Frame ◽  
Coding Region ◽  
Reading Frame ◽  
L1 Protein

Emerging advances in cancer therapy have transformed the landscape towards cancer immunotherapy regimens. Recent discoveries have resulted in the development of clinical immune checkpoint inhibitors that are ‘game-changers’ for cancer immunotherapy. Here we show that eEF2K, an atypical protein kinase that negatively modulates the elongation stage of protein synthesis, promotes the synthesis of PD-L1, an immune checkpoint protein which helps cancer cells to escape from immunosurveillance. Ablation of eEF2K in prostate and lung cancer cells markedly reduced the expression levels of the PD-L1 protein. We show that eEF2K promotes the association of PD-L1 mRNAs with translationally active polyribosomes and that translation of the PD-L1 mRNA is regulated by a uORF (upstream open reading-frame) within its 5′-UTR (5′-untranslated region) which starts with a non-canonical CUG as the initiation codon. This inhibitory effect is attenuated by eEF2K thereby allowing higher levels of translation of the PD-L1 coding region and enhanced expression of the PD-L1 protein. Moreover, eEF2K-depleted cancer cells are more vulnerable to immune attack by natural killer cells. Therefore, control of translation elongation can modulate the translation of this specific mRNA, one which contains an uORF that starts with CUG, and perhaps others that contain a similar feature. Taken together, our data reveal that eEF2K regulates PD-L1 expression at the level of the translation of its mRNA by virtue of a uORF in its 5′-region. This, and other roles of eEF2K in cancer cell biology (e.g. in cell survival and migration), may be exploited for the design of future therapeutic strategies.

scholarly journals IRF-1 expression induces apoptosis and inhibits tumor growth in mouse mammary cancer cells in vitro and in vivo

Oncogene ◽  
2004 ◽  
Vol 23 (5) ◽  
pp. 1125-1135 ◽  
Author(s):  
Peter K M Kim ◽  
Michaele Armstrong ◽  
Ye Liu ◽  
Peng Yan ◽  
Brian Bucher ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Cancer Cells ◽  
Mammary Cancer ◽  
Mammary Cancer Cells

scholarly journals SNHG6 Promotes Tumor Growth via Repression of P21 in Colorectal Cancer

2018 ◽  
Vol 49 (2) ◽  
pp. 463-478 ◽  
Author(s):  
Zhaoming Li ◽  
Ran Qiu ◽  
Xia Qiu ◽  
Tian Tian
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Tumor Formation ◽  
Cell Counting ◽  
Advanced Tumor Stage ◽  
Advanced Tumor ◽  
Colorectal Cancer Cells ◽  
P21 Promoter

Background/Aims: SNHG6 (Small Nucleolar RNA Host Gene 6) is a novel non-coding RNA (ncRNA) and its cellular function is largely unknown. Methods: Cell Counting Kit-8 (CCK-8) cell growth assay, colony formation and flow cytometry were used to determine colorectal cancer cell proliferation, cell cycle progression and apoptosis in vitro. The xenograft tumor formation assay in nude mice was established to evaluate tumor growth in vivo. RNA immunopreciptation (RIP) analysis was performed to examine whether SNHG6 could bind to EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit), and chromatin immunoprecipitation (ChIP) assay was conducted to examine whether SNHG6 could repress p21 transcription by recruiting EZH2 to the p21 promoter. Results: Here we found that SNHG6 was upregulated and its expression levels were positively correlated with advanced tumor stage in colorectal cancer. Survival analysis suggested that higher expression of SNHG6 predicted poor prognosis in patients with colorectal cancer. Functional studies indicated that SNHG6 could promote cell proliferation via a direct suppression of p21 expression in colorectal cancer cells. Moreover, SNHG6 repressed p21 transcription through recruiting EZH2 to the p21 promoter in colorectal cancer cells. Conclusion: Taken together, our study demonstrates that SNHG6 promotes tumor growth via repression of p21 in colorectal cancer, which may provide a promising target for novel anticancer therapeutics.

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