Exosomal Linc-ROR Mediates Crosstalk between Cancer Cells and Adipocytes to Promote Tumor Growth in Pancreatic Cancer

Pancreatic adenocarcinoma (PDAC) is one of the most deadly cancers in the Western world because of a lack of early diagnostic markers and efficient therapeutics. At the time of diagnosis, more than 80% of patients have metastasis or locally advanced cancer and are therefore not eligible for surgical resection. Pancreatic cancer cells also harbour a high resistance to chemotherapeutic drugs such as gemcitabine that is one of the main palliative treatments for PDAC. Proteins involved in TGF-β signaling pathway (SMAD4 or TGF-βRII) are frequently mutated in PDAC (50–80%). TGF-β signalling pathway plays antagonistic roles during carcinogenesis by initially inhibiting epithelial growth and later promoting the progression of advanced tumors and thus emerged as both tumor suppressor and oncogenic pathways. In order to decipher the role of TGF-β in pancreatic carcinogenesis and chemoresistance, we generated CAPAN-1 and CAPAN-2 cell lines knocked down for TGF-βRII (first actor of TGF-β signaling). The impact on biological properties of these TGF-βRII-KD cells was studied both in vitro and in vivo. We show that TGF-βRII silencing alters tumor growth and migration as well as resistance to gemcitabine. TGF-βRII silencing also leads to S727 STAT3 and S63 c-Jun phosphorylation, decrease of MRP3 and increase of MRP4 ABC transporter expression and induction of a partial EMT phenotype. These markers associated with TGF-β signaling pathways may thus appear as potent therapeutic tools to better treat/manage pancreatic cancer.

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Abstract 504: miR-484 acts as an “oncomiR” in triple negative breast cancer cells to promote tumor growth and progression by targeting HOXA5

10.1158/1538-7445.am2018-504 ◽

2018 ◽

Author(s):

Nashwa N. Kabil ◽

Recep Bayraktar ◽

Cristina Ivan ◽

Nermin Kahraman ◽

Hamada A. Mokhlis ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Triple Negative Breast Cancer ◽

Breast Cancer Cells ◽

Triple Negative ◽

Promote Tumor Growth

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IL23-Producing Human Lung Cancer Cells Promote Tumor Growth via Conversion of Innate Lymphoid Cell 1 (ILC1) into ILC3

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-18-3458 ◽

2019 ◽

Vol 25 (13) ◽

pp. 4026-4037 ◽

Cited By ~ 12

Author(s):

Jaemoon Koh ◽

Hye Young Kim ◽

Youngha Lee ◽

In Kyu Park ◽

Chang Hyun Kang ◽

...

Keyword(s):

Lung Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Lymphoid Cell ◽

Human Lung ◽

Lung Cancer Cells ◽

Human Lung Cancer ◽

Innate Lymphoid Cell ◽

Promote Tumor Growth ◽

Human Lung Cancer Cells

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O-GlcNAcylation of PGK1 coordinates glycolysis and TCA cycle to promote tumor growth

Nature Communications ◽

10.1038/s41467-019-13601-8 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 10

Author(s):

Hao Nie ◽

Haixing Ju ◽

Jiayi Fan ◽

Xiaoliu Shi ◽

Yaxian Cheng ◽

...

Keyword(s):

Tumor Growth ◽

Cancer Cells ◽

Tumor Development ◽

Lactate Production ◽

Phosphoglycerate Kinase ◽

Tca Cycle ◽

Human Colon ◽

Colon Cancers ◽

The Tca Cycle ◽

Promote Tumor Growth

AbstractMany cancer cells display enhanced glycolysis and suppressed mitochondrial metabolism. This phenomenon, known as the Warburg effect, is critical for tumor development. However, how cancer cells coordinate glucose metabolism through glycolysis and the mitochondrial tricarboxylic acid (TCA) cycle is largely unknown. We demonstrate here that phosphoglycerate kinase 1 (PGK1), the first ATP-producing enzyme in glycolysis, is reversibly and dynamically modified with O-linked N-acetylglucosamine (O-GlcNAc) at threonine 255 (T255). O-GlcNAcylation activates PGK1 activity to enhance lactate production, and simultaneously induces PGK1 translocation into mitochondria. Inside mitochondria, PGK1 acts as a kinase to inhibit pyruvate dehydrogenase (PDH) complex to reduce oxidative phosphorylation. Blocking T255 O-GlcNAcylation of PGK1 decreases colon cancer cell proliferation, suppresses glycolysis, enhances the TCA cycle, and inhibits tumor growth in xenograft models. Furthermore, PGK1 O-GlcNAcylation levels are elevated in human colon cancers. This study highlights O-GlcNAcylation as an important signal for coordinating glycolysis and the TCA cycle to promote tumorigenesis.

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Future Therapeutic Directions for Smac-Mimetics

Cells ◽

10.3390/cells9020406 ◽

2020 ◽

Vol 9 (2) ◽

pp. 406 ◽

Cited By ~ 10

Author(s):

Emma Morrish ◽

Gabriela Brumatti ◽

John Silke

Keyword(s):

Clinical Trials ◽

Cell Death ◽

Tumor Growth ◽

Cancer Cells ◽

Inhibitor Of Apoptosis ◽

Growth Strategies ◽

Promote Tumor Growth ◽

Cell Death Program ◽

Smac Mimetics ◽

Promote Cell Death

It is well accepted that the ability of cancer cells to circumvent the cell death program that untransformed cells are subject to helps promote tumor growth. Strategies designed to reinstate the cell death program in cancer cells have therefore been investigated for decades. Overexpression of members of the Inhibitor of APoptosis (IAP) protein family is one possible mechanism hindering the death of cancer cells. To promote cell death, drugs that mimic natural IAP antagonists, such as second mitochondria-derived activator of caspases (Smac/DIABLO) were developed. Smac-Mimetics (SMs) have entered clinical trials for hematological and solid cancers, unfortunately with variable and limited results so far. This review explores the use of SMs for the treatment of cancer, their potential to synergize with up-coming treatments and, finally, discusses the challenges and optimism facing this strategy.

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shRNA-MEDIATED KNOCKDOWN OF CCK mRNA IN PANCREATIC CANCER CELLS DOES NOT ALTER IN VIVO TUMOR GROWTH

Pancreas ◽

10.1097/01.mpa.0000335337.35708.32 ◽

2008 ◽

Vol 37 (4) ◽

pp. 484

Author(s):

G. Matters ◽

C. McGovern ◽

J. Harms ◽

K. Markovic ◽

K. Anson ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Pancreatic Cancer Cells

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Inhibition of cMET in an experimental model of pancreatic cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.4_suppl.185 ◽

2013 ◽

Vol 31 (4_suppl) ◽

pp. 185-185

Author(s):

Sven A. Lang ◽

Franziska Brandes ◽

Edward K. Geissler

Keyword(s):

Pancreatic Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Pancreatic Cancer Cell ◽

Cancer Cell Lines ◽

Human Pancreatic Cancer ◽

Oncogenic Signaling

185 Background: In human pancreatic cancer, expression of cMET is associated with poor survival. So far, activation/expression of cMET by hepatocyte growth factor (HGF) has been shown to induce proliferation and motility in cancer cells. Therefore, we hypothesized that inhibition of cMET in human pancreatic cancer cell lines impairs oncogenic signaling and tumor growth. Methods: Pancreatic cancer cell lines (HPAF-II, MiaPaCa2, L3.6pl, BxPC3, Panc02) and the cMET inhibitor INC280 (Novartis Oncology, Basel) were used. MiaPaCa2 and L3.6pl pancreatic cancer cells were grown with gemcitabine up to 500 and 250 nM, respectively (then called MiaPaCa2(G500) and L3.6pl(G250)). MTT and Boyden Chamber assays were used to determine effects of INC280 on growth and motility of cells in vitro. Expression of growth factor receptors, activation of signaling intermediates and expression of transcription factors were assessed by Western blotting. Finally, in vitro results were validated in an orthotopic tumor model using L3.6pl pancreatic cancer cell line. Results: All pancreatic cancer cell lines showed expression of cMET. In vitro treatment of cancer cells with INC280 led to a minor, dose-dependent inhibition of growth even when cells were supplemented with HGF. In contrast, migration assays showed a significant reduction of cancer cell motility upon INC280 when cells were stimulated with HGF (P<0.05). Regarding oncogenic signaling, INC280 led to inhibition of HGF-induced phosphorylation of AKT, ERK and FAK. In addition, c-Myc expression was diminished in cancer cells. Interestingly, gemcitabine resistant cell line MiaPaCa2(G500) showed higher cMET expression levels compared to the normal MiaPaCa2. Stimulation of MiaPaCa2(G500) with HGF led to strong induction of oncogenic signaling and tumor cell motility, an effect that was significantly diminished by INC280. Moreover, results from in vivo experiments show that therapy with INC280 (10 mg/kg/d) significantly reduces tumor growth as determined by final tumor weight (P<0.05). Conclusions: In pancreatic cancer cell lines, targeting cMET with INC280 abrogates oncogenic signaling in vitro and impairs tumor growth in vivo. Therefore, the concept of cMET inhibition warrants further preclinical evaluation.

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