Antisense Inhibition of Methylenetetrahydrofolate Reductase Reduces Cancer Cell Survival In vitro and Tumor Growth In vivo

Metastatic breast cancer in bone is incurable and there is an urgent need to develop new therapeutic approaches to improve survival. Key to this is understanding the mechanisms governing cancer cell survival and growth in bone, which involves interplay between malignant and accessory cell types. Here, we performed a cellular and molecular comparison of the bone microenvironment in mouse models representing either metastatic indolence or growth, to identify mechanisms regulating cancer cell survival and fate. In vivo, we show that regardless of their fate, breast cancer cells in bone occupy niches rich in osteoblastic cells. As the number of osteoblasts in bone declines, so does the ability to sustain large numbers of breast cancer cells and support metastatic outgrowth. In vitro, osteoblasts protected breast cancer cells from death induced by cell stress and signaling via gap junctions was found to provide important juxtacrine protective mechanisms between osteoblasts and both MDA-MB-231 (TNBC) and MCF7 (ER+) breast cancer cells. Combined with mathematical modelling, these findings indicate that the fate of DTCs is not controlled through the association with specific vessel subtypes. Instead, numbers of osteoblasts dictate availability of protective niches which breast cancer cells can colonize prior to stimulation of metastatic outgrowth.

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TMEM52B suppression promotes cancer cell survival and invasion through modulating E-cadherin stability and EGFR activity

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01828-7 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Yunhee Lee ◽

Dongjoon Ko ◽

Junghwa Yoon ◽

Younghoon Lee ◽

Semi Kim

Keyword(s):

Tumor Growth ◽

Cell Survival ◽

Cancer Cell ◽

Molecular Mechanisms ◽

The Cancer Genome Atlas ◽

In Vivo Studies ◽

Mesenchymal Transition ◽

E Cadherin

Abstract Background TMEM52B is a novel gene broadly expressed in a variety of normal human tissues. However, the biological function of TMEM52B expression in cancer is largely unknown. Methods The effects of TMEM52B on tumor growth and metastasis were investigated in vitro and in vivo, and the underlying biological and molecular mechanisms involved in this process were evaluated. Clinical datasets from KmPlotter and The Cancer Genome Atlas (TCGA) were analyzed in relation to TMEM52B expression and function. Results Suppression of TMEM52B in colon cancer cells promoted cancer cell epithelial-mesenchymal transition (EMT), invasion, and survival in vitro. Similarly, in vivo studies showed increased tumor growth and circulating tumor cell survival (early metastasis). ERK1/2, JNK, and AKT signaling pathways were involved in TMEM52B suppression-induced invasiveness and cell survival. TMEM52B suppression promoted activation and internalization of epidermal growth factor receptor (EGFR) with enhanced downstream signaling activity, leading to enhanced cell survival and invasion. In addition, TMEM52B suppression reduced E-cadherin stability, likely due to a reduced association between it and E-cadherin, which led to enhanced β-catenin transcriptional activity. Concomitantly, TMEM52B suppression promoted generation of soluble E-cadherin fragments, contributing to the activation of EGFR. Clinical data showed that high TMEM52B expression correlated with increased patient survival in multiple types of cancer, including breast, lung, kidney, and rectal cancers, and suggested a correlation between TMEM52B and E-cadherin. Conclusions These findings suggest that TMEM52B is a novel modulator of the interplay between E-cadherin and EGFR. It is possible that TMEM52B functions as a tumor-suppressor that could potentially be used as a novel prognostic marker for cancer.

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ATM inhibition drives metabolic adaptation via induction of macropinocytosis

10.1101/2020.04.06.027565 ◽

2020 ◽

Cited By ~ 1

Author(s):

Chi-Wei Chen ◽

Raquel Buj ◽

Erika S. Dahl ◽

Kelly E. Leon ◽

Erika L. Varner ◽

...

Keyword(s):

Cell Death ◽

Cell Survival ◽

Cancer Cell ◽

Metabolic Reprogramming ◽

Metabolic Adaptation ◽

Dependent Manner ◽

Cancer Cell Survival ◽

Branched Chain

SummaryMacropinocytosis is a nonspecific endocytic process that enhances cancer cell survival under nutrient-poor conditions. Ataxia-Telangiectasia mutated (ATM) is a tumor suppressor that plays a role in cellular metabolic reprogramming. We report that suppression of ATM increases macropinocytosis in an AMPK-dependent manner to promote cancer cell survival in nutrient-poor conditions. Combined inhibition of ATM and macropinocytosis suppressed proliferation and induced cell death both in vitro and in vivo. Metabolite analysis of the ascites and interstitial fluid from tumors indicated decreased branched chain amino acids (BCAAs) in the microenvironment of ATM-inhibited tumors. Supplementation of ATM inhibitor-treated cells with BCAAs abrogated AMPK phosphorylation and macropinocytosis and rescued the cell death that occurs due to combined inhibition of ATM and macropinocytosis. These data reveal a novel molecular basis of ATM-mediated tumor suppression whereby loss of ATM promotes pro-tumorigenic uptake of nutrients to promote cancer cell survival and reveal a metabolic vulnerability of ATM-inhibited cells.

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Knock-down of methylenetetrahydrofolate reductase reduces gastric cancer cell survival: An in vitro study

Cell Biology International ◽

10.1016/j.cellbi.2008.03.018 ◽

2008 ◽

Vol 32 (8) ◽

pp. 879-887 ◽

Cited By ~ 6

Author(s):

D SUN ◽

Y WENG ◽

Y CHEN ◽

R LU ◽

X WANG ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Survival ◽

Cancer Cell ◽

Gastric Cancer Cell ◽

Methylenetetrahydrofolate Reductase ◽

In Vitro Study ◽

Vitro Study ◽

Knock Down ◽

Cancer Cell Survival

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Functional expression of sodium-glucose transporters in cancer

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1511698112 ◽

2015 ◽

Vol 112 (30) ◽

pp. E4111-E4119 ◽

Cited By ~ 100

Author(s):

Claudio Scafoglio ◽

Bruce A. Hirayama ◽

Vladimir Kepe ◽

Jie Liu ◽

Chiara Ghezzi ◽

...

Keyword(s):

Cell Survival ◽

Glucose Uptake ◽

Cancer Cell ◽

Pet Imaging ◽

Xenograft Model ◽

Glucose Transporters ◽

Functional Expression ◽

Sglt2 Inhibitors ◽

Cancer Cell Survival

Glucose is a major metabolic substrate required for cancer cell survival and growth. It is mainly imported into cells by facilitated glucose transporters (GLUTs). Here we demonstrate the importance of another glucose import system, the sodium-dependent glucose transporters (SGLTs), in pancreatic and prostate adenocarcinomas, and investigate their role in cancer cell survival. Three experimental approaches were used: (i) immunohistochemical mapping of SGLT1 and SGLT2 distribution in tumors; (ii) measurement of glucose uptake in fresh isolated tumors using an SGLT-specific radioactive glucose analog, α-methyl-4-deoxy-4-[18F]fluoro-d-glucopyranoside (Me4FDG), which is not transported by GLUTs; and (iii) measurement of in vivo SGLT activity in mouse models of pancreatic and prostate cancer using Me4FDG-PET imaging. We found that SGLT2 is functionally expressed in pancreatic and prostate adenocarcinomas, and provide evidence that SGLT2 inhibitors block glucose uptake and reduce tumor growth and survival in a xenograft model of pancreatic cancer. We suggest that Me4FDG-PET imaging may be used to diagnose and stage pancreatic and prostate cancers, and that SGLT2 inhibitors, currently in use for treating diabetes, may be useful for cancer therapy.

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Abstract 2050: Cell penetrating peptide, ST101, disrupts ATF5 regulation of anti-apoptotic Bcl-2 family proteins, resulting in induction of cancer cell death in vitro and tumor growth inhibition/regression in vivo

10.1158/1538-7445.sabcs18-2050 ◽

2019 ◽

Author(s):

Jim A. Rotolo ◽

Rick Ramirez ◽

Mark Koester ◽

Siok Leong ◽

Lila Ghamsari ◽

...

Keyword(s):

Cell Death ◽

Tumor Growth ◽

Growth Inhibition ◽

Cancer Cell ◽

Tumor Growth Inhibition ◽

Cell Penetrating Peptide ◽

Cancer Cell Death ◽

Cell Penetrating

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mTORC2 promotes cell survival through c-Myc–dependent up-regulation of E2F1

The Journal of Cell Biology ◽

10.1083/jcb.201411128 ◽

2015 ◽

Vol 211 (1) ◽

pp. 105-122 ◽

Cited By ~ 17

Author(s):

Zhipeng Zou ◽

Juan Chen ◽

Anling Liu ◽

Xuan Zhou ◽

Qiancheng Song ◽

...

Keyword(s):

Cell Survival ◽

Tumor Model ◽

Xenograft Tumor ◽

In Vivo Experiments ◽

Xenograft Tumor Model ◽

Cancer Cell Survival ◽

Consequent Reduction ◽

Dependent Mechanism

Previous studies have reported that mTORC2 promotes cell survival through phosphorylating AKT and enhancing its activity. We reveal another mechanism by which mTORC2 controls apoptosis. Inactivation of mTORC2 promotes binding of CIP2A to PP2A, leading to reduced PP2A activity toward c-Myc serine 62 and, consequently, enhancement of c-Myc phosphorylation and expression. Increased c-Myc activity induces transcription of pri-miR-9-2/miR-9-3p, in turn inhibiting expression of E2F1, a transcriptional factor critical for cancer cell survival and tumor progression, resulting in enhanced apoptosis. In vivo experiments using B cell–specific mTORC2 (rapamycin-insensitive companion of mTOR) deletion mice and a xenograft tumor model confirmed that inactivation of mTORC2 causes up-regulation of c-Myc and miR-9-3p, down-regulation of E2F1, and consequent reduction in cell survival. Conversely, Antagomir-9-3p reversed mTORC1/2 inhibitor–potentiated E2F1 suppression and resultant apoptosis in xenograft tumors. Our in vitro and in vivo findings collectively demonstrate that mTORC2 promotes cell survival by stimulating E2F1 expression through a c-Myc– and miR-9-3p–dependent mechanism.

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SOX4 promotes the growth and metastasis of breast cancer

10.21203/rs.3.rs-35881/v2 ◽

2020 ◽

Author(s):

Jing Zhang ◽

Chunhua Xiao ◽

Zhenbo Feng ◽

Yun Gong ◽

Baohua Sun ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

Lymph Nodes ◽

Cell Viability ◽

Cancer Cell ◽

Chemotherapeutic Agents ◽

Migration And Invasion ◽

Primary Tumors

Abstract Purpose Increasing evidence has shown that the transcription factor SOX4 is closely associated with the development and progression of many malignant tumors. However, the effect of SOX4 on breast cancer is unclear. In this study, we purposed to investigate the role of SOX4 in the growth and metastasis in breast cancer and the underlying mechanism. Moreover, the effect of SOX4 on cancer cell resistance to chemotherapeutic agents was also evaluated in vitro and in vivo . Methods We used lentivirus technique to ectopically express SOX4 in MDA-MB-231 and SUM149 cells or knockdown SOX4 in BT474 cells, and examined the effect of these changes on various cellular functions. MTT assay was used to determine the cell viability as well as resistance to chemotherapeutic agents. The regulation of SOX4 on epithelial-mesenchymal transition (EMT)-related genes was analyzed using qRT-PCR. The binding of SOX4 to the CXCR7 gene was demonstrated using chromatin immunoprecipitation assay and dual-luciferase reporter activity assay. The effect of SOX4/CXCR7 axis on metastasis was examined using Transwell migration and Matrigel invasion assays. The expression of SOX4/CXCR7 in primary tumors and metastatic foci in lymph nodes was assessed using immunohistochemistry. Cellular morphology was investigated under phase contrast microscope and transmission electron microscopy. Moreover, the effect of SOX4 on tumor growth, metastasis, and resistance to chemotherapy was also studied in vivo by using bioluminescent imaging. Results SOX4 increased breast cancer cell viability, migration, and invasion in vitro and enhanced tumor growth and metastasis in vivo . It regulated EMT-related genes and bound to CXCR7 promoter to upregulate CXCR7 transcription. Both SOX4 and CXCR7 were highly expressed in human primary tumors and metastatic foci in lymph nodes. Treatment of breast cancer cells with the CXCR7 inhibitor CCX771 reversed the SOX4 effect on cell migration and invasion. Ectopic expression of SOX4 increased the susceptibility of cells to paclitaxel. Conclusions SOX4 plays an important role in the growth and metastasis of breast cancer. SOX4/CXCR7 may serve as potential therapeutic targets for the treatment. Paclitaxel may be a good therapeutic option if the expression level of SOX4 is high.

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Signal transducer and activator of transcription 5b (STAT5b) as a novel target for anti-neoplastic therapy in human pancreatic cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.4_suppl.217 ◽

2011 ◽

Vol 29 (4_suppl) ◽

pp. 217-217

Author(s):

C. Moser ◽

P. Ruemle ◽

H. Schenk ◽

E. K. Geissler ◽

H. J. Schlitt ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Growth ◽

Cell Motility ◽

Cancer Cell ◽

Human Pancreatic Cancer ◽

Signal Transducer ◽

Tumor Vascularization ◽

Knock Down

217 Background: Activation of signal transducer and activator of transcription 5b (STAT5b) has been associated with tumor growth and metastases in various tumor entities. A number of cytokines, growth factors, and oncogenes that can induce STAT5b activity are also implicated in pancreatic cancer growth and metastases. Hence, we sought to determine STAT5b expression in human pancreatic cancer specimen and effects of selective STAT5b inhibition on pancreatic cancer cells. Methods: Expression of STAT5b in human pancreatic adenocarcinomas was determined by immunohistochemistry. For in vitro experiments, human pancreatic cancer cell lines (BxPC-3, HPAF-II, L3.6pl) were used. Cancer cells were transfected with STAT5b shRNA plasmid to create stable STAT5b knock-down. Effects of STAT5b inhibition on growth and motility of tumor cells was investigated by MTT and modified Boyden chamber assays. In vivo effects of STAT5b blockade were determined in subcutaneous mouse model. Results: Nuclear expression of STAT5b was detected in 42/80 human pancreatic adenocarcinomas. In human cancer cell lines, stable knock-down of STAT5b had no effect on growth of tumor cells in vitro. However, tumor cell motility was significantly reduced upon STAT5b blockade (p<0.05). Moreover, expression of various signaling intermediates and transcription factors including c-myc was impaired upon STAT5b knock-down. In a subcutaneous tumor model, inhibition of STAT5b led to significantly reduced tumor growth (p<0.05) which was also reflected by final tumor weights (p<0.05). Furthermore, as revealed by immunohistochemistry, blockade of STAT5b significantly reduced tumor vascularization in vivo (p<0.05). Conclusions: STAT5b is expressed in human pancreatic adenocarcinomas. Blockade of STAT5b impairs cancer cell motility in vitro, suggesting antimetastatic potential. Moreover, inhibition of STAT5b significantly reduces tumor growth and tumor vascularization in vivo. Hence, STAT5b might be an interesting target for antineoplastic therapy in human pancreatic cancer. No significant financial relationships to disclose.

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