Intracellular targeting of the oncogenic MUC1-C protein with a GO-203 nanoparticle formulation overcomes MCL-1- and BFL-1-mediated resistance in human carcinoma cells.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14053-e14053
Author(s):  
Masayuki Hiraki ◽  
Caining Jin ◽  
Maroof Alam ◽  
Takahiro Maeda ◽  
Masaru Murata ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Polymeric Nanoparticles ◽  
In Vivo Studies ◽  
Parental Cancer ◽  
Mucin 1 ◽  
Aberrant Expression ◽  
Human Carcinoma ◽  
Resistant Cells

e14053 Background: Aberrant expression of MCL-1 and BFL-1, the pro-survival members of the Bcl-2 family, is a major cause of drug resistance in human cancers. Mucin 1 (MUC1) is a heterodimeric oncoprotein that is aberrantly expressed in most human carcinomas. Notably, there is no known relationship between the oncogenic MUC1 C-terminal subunit (MUC1-C) and these anti-apoptotic proteins. Methods: MUC1-C was targeted in breast, lung and colon cancer cells by a stable shRNA, a tetracycline-inducible shRNA, or a pharmacologic peptide inhibitor GO-203. MCL-1 was inhibited by siRNA or the MS-1 peptide. In vitro and in vivo studies were conducted using our polymeric nanoparticles (NPs) for intracellular delivery of peptide cargos. Cells were selected for resistance to ABT-737 or ABT-263, which target BCL-2, BCL-XL and BCL-w, but not MCL-1 and BFL-1. Results: Targeting MCL-1 with MS-1/NPs inhibited the survival of parental cancer cells in vitro and in vivo, and was associated with upregulation of BFL-1 levels. In addition, MS-1/NPs treatment had limited effects on ABT-resistant cells because of increased BFL-1 expression. Importantly, we found that targeting MUC1-C is associated with suppression of both MCL-1 and BFL-1. Mechanistically, MUC1-C (i) stabilizes MCL-1 by activating the MEK→ERK and PI3K→AKT pathways, and (ii) induces BFL-1 through the NF-κB p65 pathway. Treatment with GO-203/NPs suppressed proliferation of parental and ABT-resistant cells. In addition, we show that combining GO-203 with ABT-737 is synergistic in inhibiting survival of parental and ABT-resistant cells. Conclusions: These findings demonstrate that targeting MUC1-C with GO-203/NPs is a potential strategy for abrogating MCL-1- and BFL-1-mediated resistance.

scholarly journals Splicing factor USP39 promotes ovarian cancer malignancy through maintaining efficient splicing of oncogenic HMGA2

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Shourong Wang ◽  
Zixiang Wang ◽  
Jieyin Li ◽  
Junchao Qin ◽  
Jianping Song ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Malignant Tumors ◽  
Splicing Factor ◽  
Ovarian Cancer Cells ◽  
Nuclear Speckles ◽  
Aberrant Expression ◽  
Intergenic Regions

AbstractAberrant expression of splicing factors was found to promote tumorigenesis and the development of human malignant tumors. Nevertheless, the underlying mechanisms and functional relevance remain elusive. We here show that USP39, a component of the spliceosome, is frequently overexpressed in high-grade serous ovarian carcinoma (HGSOC) and that an elevated level of USP39 is associated with a poor prognosis. USP39 promotes proliferation/invasion in vitro and tumor growth in vivo. Importantly, USP39 was transcriptionally activated by the oncogene protein c-MYC in ovarian cancer cells. We further demonstrated that USP39 colocalizes with spliceosome components in nuclear speckles. Transcriptomic analysis revealed that USP39 deletion led to globally impaired splicing that is characterized by skipped exons and overrepresentation of introns and intergenic regions. Furthermore, RNA immunoprecipitation sequencing showed that USP39 preferentially binds to exon-intron regions near 5′ and 3′ splicing sites. In particular, USP39 facilitates efficient splicing of HMGA2 and thereby increases the malignancy of ovarian cancer cells. Taken together, our results indicate that USP39 functions as an oncogenic splicing factor in ovarian cancer and represents a potential target for ovarian cancer therapy.

scholarly journals Tip60 Suppresses Cholangiocarcinoma Proliferation and Metastasis via PI3k-AKT

2018 ◽  
Vol 50 (2) ◽  
pp. 612-628 ◽  
Author(s):  
Yaodong Zhang ◽  
Guwei Ji ◽  
Sheng Han ◽  
Zicheng Shao ◽  
Zefa Lu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cancer Progression ◽  
Venous Invasion ◽  
In Vivo Studies ◽  
Akt Pathway ◽  
Rank Test ◽  
Aberrant Expression ◽  
Proliferation And Metastasis

Background/Aims: Aberrant expression of Tip60 is associated with progression in many cancers. However, the role of Tip60 in cancer progression remains contradictory. The aim of this study was to investigate the clinical significance, biological functions and underlying mechanisms of Tip60 deregulation in cholangiocarcinoma (CCA) for the first time. Methods: Quantitative real-time PCR (QRT-PCR), western blotting and immunohistochemistry staining (IHC) were carried out to measure Tip60 expression in CCA tissues and cell lines. Kaplan–Meier analysis and the log-rank test were used for survival analysis. In vitro, cell proliferation was evaluated by flow cytometry and CCK-8, colony formation, and EDU assays. Migration/ invasion was evaluated by trans-well assays. Phosphokinase array was used to confirm the dominant signal regulated by Tip60. Tumor growth and metastasis were demonstrated in vivo using a mouse model. Results: Tip60 was notably downregulated in CCA tissues, which was associated with greater tumor size, venous invasion, and TNM stage. Down-regulation of Tip60 was associated with tumor progression and poorer survival in CCA patients. In vitro and in vivo studies demonstrated that Tip60 suppressed growth and metastasis throughout the progression of CCA. We further identified the PI3K/AKT pathway as a dominant signal of Tip60 and suggested that Tip60 regulated CCA cell proliferation and metastasis via PT3K-AKT pathway. Pearson analysis revealed that PTEN was positively correlated with the Tip60 level in CCA tissues. Conclusion: Tip60, as a tumor suppressor in CCA via the PI3K/AKT pathway, might be a promising therapeutic target or prognostic marker for CCA.

Downregulation of CCKBR Expression Inhibits the Proliferation of Gastric Cancer Cells, Revealing a Potential Target for Immunotoxin Therapy

2022 ◽  
Vol 22 ◽  
Author(s):  
Meng Li ◽  
Jiang Chang ◽  
Honglin Ren ◽  
Defeng Song ◽  
Jian Guo ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Gastric Cancer Cells ◽  
Aberrant Expression ◽  
Promising Target ◽  
The Impact

Background Increased CCKBR expression density or frequency has been reported in many neoplasms. Objective We aimed to investigate whether CCKBR drives the growth of gastric cancer (GC) and its potential as a therapeutic target of immunotoxins. Methods A lentiviral interference system was used to generate CCKBR-knockdown gastric cancer cells. Cell Counting Kit-8 and clonogenic assays were used to evaluate cell proliferation. Wound-healing and cell invasion assays were performed to evaluate cell mobility. Cell cycle was analyzed by flow cytometry. Tumor growth in vivo was investigated using a heterologous tumor transplantation model in nude mice. In addition, we generated the immunotoxin FQ17P and evaluated the combining capacity and tumor cytotoxicity of FQ17P in vitro. Results Stable downregulation of CCKBR expression resulted in reduced proliferation, migration and invasion of BGC-823 and SGC-7901 cells. The impact of CCKBR on gastric cancer cells was further verified through CCKBR overexpression studies. Downregulation of CCKBR expression also inhibited the growth of gastric tumors in vivo. Furthermore, FQ17P killed CCKBR-overexpressing GC cells by specifically binding to CCKBR on the tumor cell surface. Conclusion The CCKBR protein drives the growth, migration, and invasion of gastric cancer cells, and it might be a promising target for immunotoxin therapy based on its aberrant expression, functional binding interactions with gastrin, and subsequent internalization.

scholarly journals DEPDC1B is a tumor promotor in development of bladder cancer through targeting SHC1

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Chin-Hui Lai ◽  
Kexin Xu ◽  
Jianhua Zhou ◽  
Mingrui Wang ◽  
Weiyu Zhang ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cancer Cells ◽  
Malignant Tumors ◽  
Tumor Grade ◽  
In Vivo Studies ◽  
Mechanistic Study ◽  
Tumor Promotor ◽  
Bladder Cancer Cells

AbstractBladder cancer is one of the most commonly diagnosed malignant tumors in the urinary system and causes a massive cancer-related death. DEPDC1B is a DEP domain-containing protein that has been found to be associated with a variety of human cancers. This study aimed to explore the role and mechanism of DEPDC1B in the development of bladder cancer. The analysis of clinical specimens revealed the upregulated expression of DEPDC1B in bladder cancer, which was positively related to tumor grade. In vitro and in vivo studies showed that DEPDC1B knockdown could inhibit the growth of bladder cancer cells or xenografts in mice. The suppression of bladder cancer by DEPDC1B was executed through inhibiting cell proliferation, cell migration, and promoting cell apoptosis. Moreover, a mechanistic study found that SHC1 may be an important route through which DEPDC1B regulates the development of bladder cancer. Knockdown of SHC1 in DEPDC1B-overexpressed cancer cells could abolish the promotion effects induced by DEPDC1B. In conclusion, DEPDC1B was identified as a key regulator in the development of bladder cancer, which may be used as a potential therapeutic target in the treatment of bladder cancer.

scholarly journals Targetability of hyaluronic acid nanogel to cancer cells : In vitro and in vivo studies

2017 ◽  
Vol 104 ◽  
pp. 102-113 ◽  
Author(s):  
S.S. Pedrosa ◽  
P. Pereira ◽  
A. Correia ◽  
F.M. Gama
Keyword(s):  
Hyaluronic Acid ◽  
Cancer Cells ◽  
In Vivo Studies

scholarly journals A Review of the Potential of Phytochemicals from Prunus africana (Hook f.) Kalkman Stem Bark for Chemoprevention and Chemotherapy of Prostate Cancer

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Richard Komakech ◽  
Youngmin Kang ◽  
Jun-Hwan Lee ◽  
Francis Omujal
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Treatment Options ◽  
Chemotherapeutic Agents ◽  
Sub Saharan Africa ◽  
In Vivo Studies ◽  
Prostate Cancer Cells ◽  
Prunus Africana

Prostate cancer remains one of the major causes of death worldwide. In view of the limited treatment options for patients with prostate cancer, preventive and treatment approaches based on natural compounds can play an integral role in tackling this disease. Recent evidence supports the beneficial effects of plant-derived phytochemicals as chemopreventive and chemotherapeutic agents for various cancers, including prostate cancer. Prunus africana has been used for generations in African traditional medicine to treat prostate cancer. This review examined the potential roles of the phytochemicals from P. africana, an endangered, sub-Saharan Africa plant in the chemoprevention and chemotherapy of prostate cancer. In vitro and in vivo studies have provided strong pharmacological evidence for antiprostate cancer activities of P. africana-derived phytochemicals. Through synergistic interactions between different effective phytochemicals, P. africana extracts have been shown to exhibit very strong antiandrogenic and antiangiogenic activities and have the ability to kill tumor cells via apoptotic pathways, prevent the proliferation of prostate cancer cells, and alter the signaling pathways required for the maintenance of prostate cancer cells. However, further preclinical and clinical studies ought to be done to advance and eventually use these promising phytochemicals for the prevention and chemotherapy of human prostate cancer.

Preclinical evaluation of anti-ROR1 CAR T cells employing a ROR1 binding SCFV derived from the clinical stage mab cirmtuzumab.

2020 ◽  
Vol 38 (5_suppl) ◽  
pp. 41-41
Author(s):  
Charles E. Prussak ◽  
Christopher Oh ◽  
Juliana Velez Lujan ◽  
Sharon Lam ◽  
Jieyu Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Cancer Cells ◽  
In Vivo Studies ◽  
Tumor Escape ◽  
Cancer Stemness ◽  
2Nd Generation ◽  
Car T Cells ◽  
Car T

41 Background: Chimeric antigen receptor (CAR)-modified T cells (CAR-T) were generated targeting cells expressing ROR1, which is present on many malignant cancers and has been associated with cancer stemness and chemo-resistance. The ROR1 CAR utilizes the humanized single-chain fragment variable (scFv) binding domain of UC-961 (cirmtuzumab), which exhibits high affinity and specificity for human ROR1 and has demonstrated an excellent safety profile in Phase 1 studies. Methods: CAR constructs with varying spacer regions and intracellular co-stimulatory domains, using the scFV of cirmtuzumab, were constructed and used to generate CAR-T cells from healthy donors. These ROR1 CAR-T cells were tested for cytotoxicity against lymphoid cancer cells in vitro and in vivo studies that employed immune-deficient mice engrafted with labeled human leukemia cells MEC1 or MEC1-ROR1, which had been transfected to stably express ROR1. Results: The 2nd generation and 3rd generation CAR-T-cells with analogous spacer regions were comparably potent and selectively cytotoxic for cells bearing the ROR1 target antigen. But the 2nd generation CARs demonstrated greater potency in vitro even at low effector to target ratios. For the in vivo studies, mice received a single injection of ROR1 CAR-T cells or activated T cells from the same donor as a control. The ROR1 CAR-T cells rapidly cleared the leukemic cells from the animals, whereas animals receiving control T cells or no therapy quickly succumbed to progressive disease within 3 weeks. The administered CAR-T products remained highly active following administration and could be detected for ≥ 3 months without evidence for T cell exhaustion. Conclusions: The generated CAR-T cells utilizing constructs with the Fv of cirmtuzumab, a humanized mAb highly specific for ROR1, onco-embryonic surface antigen, effectively and selectively killed neoplastic cells bearing ROR1 both in vitro and in vivo. As ROR1 expression and signaling has been associated with cancer stemness and chemo-resistance utilizing ROR1 CAR-T therapy to target cancer cells might mitigate tumor escape. These data strongly support the rationale for continued development of our ROR1 CAR-T.

scholarly journals Aspirin prevents growth and differentiation of breast cancer cells: lessons from in vitro and in vivo studies

2013 ◽  
Vol 27 (S1) ◽  
Author(s):  
Gargi Maity ◽  
Archana De ◽  
Snigdha Banerjee ◽  
Amlan Das ◽  
Sushanta Banerjee
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
In Vivo Studies
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