Increased cell apoptosis in human lung adenocarcinoma and in vivo tumor growth inhibition by RBM10, a tumor suppressor gene

AbstractCancer genome sequencing has uncovered substantial complexity in the mutational landscape of tumors. Given this complexity, experimental approaches are necessary to establish the impact of combinations of genetic alterations on tumor biology and to uncover genotype-dependent effects on drug sensitivity. In lung adenocarcinoma, EGFR mutations co-occur with many putative tumor suppressor gene alterations, however the extent to which these alterations contribute to tumor growth and their response to therapy in vivo has not been explored experimentally. By integrating a novel mouse model of oncogenic EGFR-driven Trp53-deficient lung adenocarcinoma with multiplexed CRISPR–Cas9-mediated genome editing and tumor barcode sequencing, we quantified the effects of inactivation of ten putative tumor suppressor genes. Inactivation of Apc, Rb1, or Rbm10 most strongly promoted tumor growth. Unexpectedly, inactivation of Lkb1 or Setd2 – which are the strongest drivers of tumor growth in an oncogenic Kras-driven model – reduced EGFR-driven tumor growth. These results are consistent with the relative frequency of these tumor suppressor gene alterations in human EGFR- and KRAS-driven lung adenocarcinomas. Furthermore, Keap1 inactivation reduces the sensitivity of EGFR-driven Trp53-deficient tumors to the EGFR inhibitor osimertinib. Importantly, in human EGFR/TP53 mutant lung adenocarcinomas, mutations in the KEAP1 pathway correlated with decreased time on tyrosine kinase inhibitor treatment. Our study highlights how genetic alterations can have dramatically different biological consequences depending on the oncogenic context and that the fitness landscape can shift upon drug treatment.

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Inactivation of RASSF1C during in vivo tumor growth identifies it as a tumor suppressor gene

Oncogene ◽

10.1038/sj.onc.1207789 ◽

2004 ◽

Vol 23 (35) ◽

pp. 5941-5949 ◽

Cited By ~ 43

Author(s):

Jingfeng Li ◽

Fuli Wang ◽

Alexey Protopopov ◽

Alena Malyukova ◽

Vladimir Kashuba ◽

...

Keyword(s):

Tumor Suppressor ◽

Tumor Growth ◽

Tumor Suppressor Gene ◽

Suppressor Gene

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MIR99AHG is a noncoding tumor suppressor gene in lung adenocarcinoma

Cell Death and Disease ◽

10.1038/s41419-021-03715-7 ◽

2021 ◽

Vol 12 (5) ◽

Author(s):

Chencheng Han ◽

Hong Li ◽

Zhifei Ma ◽

Guozhang Dong ◽

Qianyun Wang ◽

...

Keyword(s):

Tumor Suppressor ◽

Lung Adenocarcinoma ◽

Tumor Suppressor Gene ◽

Copy Number ◽

Mammalian Target Of Rapamycin ◽

Suppressor Gene ◽

Bioinformatics Analyses ◽

Vesicle Biogenesis

AbstractLittle is known about noncoding tumor suppressor genes. An effective way to identify these genes is by analyzing somatic copy number variation (CNV)-related noncoding genes. By integrated bioinformatics analyses of differentially expressed long noncoding RNAs (lncRNAs) and arm-level CNVs in lung adenocarcinoma (LUAD), we identified a potential antitumor gene, MIR99AHG, encoding lncRNA MIR99AHG as well as a miR-99a/let-7c/miR-125b2 cluster on chromosome 21q. All four of these transcripts were downregulated in LUAD tissues partly due to the copy number deletion of the MIR99AHG gene. Both MIR99AHG and miR-99a expression was positively correlated with the survival of LUAD patients. MIR99AHG suppressed proliferation and metastasis and promoted autophagy both in vitro and in vivo. Mechanistically, the interaction between MIR99AHG and ANXA2 could accelerate the ANXA2-induced ATG16L+ vesicle biogenesis, thus promoting phagophore assembly. Additionally, miR-99a targeted a well-known autophagy suppressor, mammalian target of rapamycin (mTOR), thereby synergistically promoting autophagy and postponing LUAD progression with MIR99AHG. In summary, MIR99AHG emerges as a noncoding tumor suppressor gene in LUAD, providing a new strategy for antitumor therapy.

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Clitocine targets Mcl-1 to induce drug-resistant human cancer cell apoptosis in vitro and tumor growth inhibition in vivo

APOPTOSIS ◽

10.1007/s10495-014-0969-0 ◽

2014 ◽

Vol 19 (5) ◽

pp. 871-882 ◽

Cited By ~ 9

Author(s):

Jian-guo Sun ◽

Hua Li ◽

Xia Li ◽

Xueli Zeng ◽

Ping Wu ◽

...

Keyword(s):

Tumor Growth ◽

Growth Inhibition ◽

Cancer Cell ◽

Cell Apoptosis ◽

Human Cancer ◽

Tumor Growth Inhibition ◽

Drug Resistant ◽

Human Cancer Cell

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Faculty Opinions recommendation of Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1002416.30570 ◽

2001 ◽

Author(s):

Martine Roussel

Keyword(s):

Cell Proliferation ◽

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Progenitor Cell ◽

Suppressor Gene ◽

Negative Regulation ◽

Progenitor Cell Proliferation

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Faculty Opinions recommendation of Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1002416.27805 ◽

2001 ◽

Author(s):

Laura Johnston

Keyword(s):

Cell Proliferation ◽

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Progenitor Cell ◽

Suppressor Gene ◽

Negative Regulation ◽

Progenitor Cell Proliferation

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The Anti-Cancer Effects of a Zotarolimus and 5-Fluorouracil Combination Treatment on A549 Cell-Derived Tumors in BALB/c Nude Mice

International Journal of Molecular Sciences ◽

10.3390/ijms22094562 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4562

Author(s):

Ching-Feng Wu ◽

Ching-Yang Wu ◽

Robin Y.-Y. Chiou ◽

Wei-Cheng Yang ◽

Chuen-Fu Lin ◽

...

Keyword(s):

Growth Factor ◽

Tumor Growth ◽

Lung Adenocarcinoma ◽

Nude Mice ◽

Transforming Growth Factor ◽

Human Lung ◽

Transforming Growth Factor Β ◽

Related Factors ◽

Human Lung Adenocarcinoma

Zotarolimus is a semi-synthetic derivative of rapamycin and a novel immunosuppressive agent used to prevent graft rejection. The pharmacological pathway of zotarolimus restricts the kinase activity of the mammalian target of rapamycin (mTOR), which potentially leads to reductions in cell division, cell growth, cell proliferation, and inflammation. These pathways have a critical influence on tumorigenesis. This study aims to examine the anti-tumor effect of zotarolimus or zotarolimus combined with 5-fluorouracil (5-FU) on A549 human lung adenocarcinoma cell line implanted in BALB/c nude mice by estimating tumor growth, apoptosis expression, inflammation, and metastasis. We established A549 xenografts in nude mice, following which we randomly divided the mice into four groups: control, 5-FU (100 mg/kg/week), zotarolimus (2 mg/kg/day), and zotarolimus combined with 5-FU. Compared the results with those for control mice, we found that mice treated with zotarolimus or zotarolimus combined with 5-FU retarded tumor growth; increased tumor apoptosis through the enhanced expression of cleaved caspase 3 and extracellular signal-regulated kinase (ERK) phosphorylation; decreased inflammation cytokines levels (e.g., IL-1β, TNF-α, and IL-6); reduced inflammation-related factors such as cyclooxygenase-2 (COX-2) protein and nuclear factor-κB (NF-κB) mRNA; enhanced anti-inflammation-related factors including IL-10 and inhibitor of NF-κB kinase α (IκBα) mRNA; and inhibited metastasis-related factors such as transforming growth factor β (TGF-β), CD44, epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF). Notably, mice treated with zotarolimus combined with 5-FU had significantly retarded tumor growth, reduced tumor size, and increased tumor inhibition compared with the groups of mice treated with 5-FU or zotarolimus alone. The in vivo study confirmed that zotarolimus or zotarolimus combined with 5-FU could retard lung adenocarcinoma growth and inhibit tumorigenesis. Zotarolimus and 5-FU were found to have an obvious synergistic tumor-inhibiting effect on lung adenocarcinoma. Therefore, both zotarolimus alone and zotarolimus combined with 5-FU may be potential anti-tumor agents for treatment of human lung adenocarcinoma.

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Highly Differentiated Anti-CD47 Antibody, AO-176, Potently Inhibits Hematologic Malignancies Alone and in Combination

Blood ◽

10.1182/blood-2019-126298 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1844-1844

Author(s):

John Richards ◽

Myriam N Bouchlaka ◽

Robyn J Puro ◽

Ben J Capoccia ◽

Ronald R Hiebsch ◽

...

Keyword(s):

Multiple Myeloma ◽

Combination Therapy ◽

Tumor Growth ◽

Growth Inhibition ◽

Tumor Cells ◽

Tumor Growth Inhibition ◽

Employment Equity ◽

Equity Ownership

AO-176 is a highly differentiated, humanized anti-CD47 IgG2 antibody that is unique among agents in this class of checkpoint inhibitors. AO-176 works by blocking the "don't eat me" signal, the standard mechanism of anti-CD47 antibodies, but also by directly killing tumor cells. Importantly, AO-176 binds preferentially to tumor cells, compared to normal cells, and binds even more potently to tumors in their acidic microenvironment (low pH). Hematological neoplasms are the fourth most frequently diagnosed cancers in both men and women and account for approximately 10% of all cancers. Here we describe AO-176, a highly differentiated anti-CD47 antibody that potently targets hematologic cancers in vitro and in vivo. As a single agent, AO-176 not only promotes phagocytosis (15-45%, EC50 = 0.33-4.1 µg/ml) of hematologic tumor cell lines (acute myeloid leukemia, non-Hodgkin's lymphoma, multiple myeloma, and T cell leukemia) but also directly targets and kills tumor cells (18-46% Annexin V positivity, EC50 = 0.63-10 µg/ml) in a non-ADCC manner. In combination with agents targeting CD20 (rituximab) or CD38 (daratumumab), AO-176 mediates enhanced phagocytosis of lymphoma and multiple myeloma cell lines, respectively. In vivo, AO-176 mediates potent monotherapy tumor growth inhibition of hematologic tumors including Raji B cell lymphoma and RPMI-8226 multiple myeloma xenograft models in a dose-dependent manner. Concomitant with tumor growth inhibition, immune cell infiltrates were observed with elevated numbers of macrophage and dendritic cells, along with increased pro-inflammatory cytokine levels in AO-176 treated animals. When combined with bortezomib, AO-176 was able to elicit complete tumor regression (100% CR in 10/10 animals treated with either 10 or 25 mg/kg AO-176 + 1 mg/kg bortezomib) with no detectable tumor out to 100 days at study termination. Overall survival was also greatly improved following combination therapy compared to animals treated with bortezomib or AO-176 alone. These data show that AO-176 exhibits promising monotherapy and combination therapy activity, both in vitro and in vivo, against hematologic cancers. These findings also add to the previously reported anti-tumor efficacy exhibited by AO-176 in solid tumor xenografts representing ovarian, gastric and breast cancer. With AO-176's highly differentiated MOA and binding characteristics, it may have the potential to improve upon the safety and efficacy profiles relative to other agents in this class. AO-176 is currently being evaluated in a Phase 1 clinical trial (NCT03834948) for the treatment of patients with select solid tumors. Disclosures Richards: Arch Oncology Inc.: Employment, Equity Ownership, Other: Salary. Bouchlaka:Arch Oncology Inc.: Consultancy, Equity Ownership. Puro:Arch Oncology Inc.: Employment, Equity Ownership. Capoccia:Arch Oncology Inc.: Employment, Equity Ownership. Hiebsch:Arch Oncology Inc.: Employment, Equity Ownership. Donio:Arch Oncology Inc.: Employment, Equity Ownership. Wilson:Arch Oncology Inc.: Employment, Equity Ownership. Chakraborty:Arch Oncology Inc.: Employment, Equity Ownership. Sung:Arch Oncology Inc.: Employment, Equity Ownership. Pereira:Arch Oncology Inc.: Employment, Equity Ownership.

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Chemical selectivity of nucleobase adduction relative to in vivo mutation sites on exon 7 fragment of p53 tumor suppressor gene

Chemical Science ◽

10.1039/c5sc01403d ◽

2015 ◽

Vol 6 (10) ◽

pp. 5554-5563 ◽

Cited By ~ 5

Author(s):

Spundana Malla ◽

Karteek Kadimisetty ◽

You-Jun Fu ◽

Dharamainder Choudhary ◽

Ingela Jansson ◽

...

Keyword(s):

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

P53 Gene ◽

Suppressor Gene ◽

P53 Tumor Suppressor ◽

P53 Tumor Suppressor Gene ◽

Chemical Selectivity

A 32-bp fragment of P53 gene reacted with benzo[a]pyrene metabolite BPDE was analyzed by LC-MS/MS. Chemically reactive sites were similar to frequently mutated codons in tumors.

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