Cigarette Smoke Induces Stem Cell Features of Pancreatic Cancer Cells via PAF1

Nimmakayala, Rama Krishna; Seshacharyulu, Parthasarathy; Lakshmanan, Imayavaramban; Chugh, Seema; Karmakar, Saswati; Vengoji, Raghupathy; Atri, Pranita; Talmon, Geoffrey A.; Lele, Subodh M.; Smith, Lynette M.; Thapa, Ishwor; Bastola, Dhundy; Ouellette, Michel; Batra, Surinder K.; Ponnusamy, Moorthy P.

doi:10.1053/j.gastro.2018.05.041

Cited by 75 publications

(61 citation statements)

References 42 publications

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“…Furthermore, recent studies have indicated that FOSL1 plays an important role in the regulation of epithelial‐mesenchymal transition, which is associated with tumor metastasis . Additionally, our data (Figure and Table ) and other published data all showed that pancreatic cancer tissues have a slightly higher expression of FOSL1 compared with normal pancreatic tissues. All of these results imply that agents that can downregulate the expression of FOSL1 might have potential to be used for the treatment of PDAC.…”

Section: Introductionsupporting

confidence: 81%

Preclinical pharmacodynamic evaluation of a new Src/FOSL1 inhibitor, LY‐1816, in pancreatic ductal adenocarcinoma

et al. 2019

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Despite tremendous efforts, the clinical prognosis of pancreatic ductal adenocarcinoma ( PDAC ) remains disappointing. There is an urgent need to develop more effective treatment strategies to improve the prognosis of patients with PDAC . In this study, we evaluate the anti‐ PDAC effects of LY ‐1816, a new multikinase inhibitor developed by us. In in vitro assays, LY ‐1816 showed significant inhibitory effects on the proliferation, migration, and invasion of human PDAC cells, and induced PDAC cell apoptosis. Western blot analysis revealed that LY ‐1816 markedly suppressed the Src signaling, and downregulated the expression of FOSL 1; FOSL 1 is an oncogene vulnerability in KRAS ‐driven pancreatic cancer. In in vivo models of PDAC xenografts (Aspc‐1 and Bxpc‐3), LY ‐1816 showed more potent antitumor activity than dasatinib and gemcitabine. Moreover, mice treated with LY ‐1816 showed a much more significant survival advantage in a metastatic model of PDAC compared with those treated with vehicle, dasatinib, or gemcitabine. These results provide effective support for the subsequent clinical evaluation of LY ‐1816 in the treatment of PDAC .

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Section: Introductionsupporting

confidence: 81%

Preclinical pharmacodynamic evaluation of a new Src/FOSL1 inhibitor, LY‐1816, in pancreatic ductal adenocarcinoma

et al. 2019

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“…Subsequently, various signalling pathways are activated, such as Wnt/‐catenin, Ras/Raf/MEK/ERK, PI3K/Akt and JAK2/Stat3, leading to the promotion of tumour cell proliferation, EMT and migration . Nicotine and its derivatives such as NNK and NNN, can not only activate nAChRs, studies have also shown that lung cancers synthesize acetylcholine (ACh) and cytokines, which acted as autocrine growth factors that stimulate nAChRs in lung cancer despite a lack of exogenous nicotine . EMT is a key initiating event in the metastatic cascades of various cancers .…”

Section: Discussionmentioning

confidence: 99%

“…[36][37][38][39][40] Nicotine and its derivatives such as NNK and NNN, can not only activate nAChRs, studies have also shown that lung cancers synthesize acetylcholine (ACh) and cytokines, which acted as autocrine growth factors that stimulate nAChRs in lung cancer despite a lack of exogenous nicotine. 41,42 EMT is a key initiating event in the metastatic cascades of various cancers. [43][44][45] The molecular mechanism of α5-nAChR in lung cancer EMT is far from clear.…”

Section: Discussionmentioning

confidence: 99%

α5‐nAChR contributes to epithelial‐mesenchymal transition and metastasis by regulating Jab1/Csn5 signalling in lung cancer

Chen

Jia

Zhang

et al. 2020

J Cellular Molecular Medi

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Recent studies have showed that α5 nicotinic acetylcholine receptor (α5‐nAChR) is closely associated with nicotine‐related lung cancer. Our previous studies also demonstrated that α5‐nAChR mediates nicotine‐induced lung carcinogenesis. However, the mechanism by which α5‐nAChR functions in lung carcinogenesis remains to be elucidated. Jab1/Csn5 is a key regulatory factor in smoking‐induced lung cancer. In this study, we explored the underlying mechanisms linking the α5‐nAChR‐Jab1/Csn5 axis with lung cancer epithelial‐mesenchymal transition (EMT) and metastasis, which may provide potential therapeutic targets for future lung cancer treatments. Our results demonstrated that the expression of α5‐nAChR was correlated with the expression of Jab1/Csn5 in lung cancer tissues and lung cancer cells. α5‐nAChR expression is associated with Jab1/Csn5 expression in lung tumour xenografts in mice. In vitro, the expression of α5‐nAChR mediated Stat3 and Jab1/Csn5 expression, significantly regulating the expression of the EMT markers, N‐cadherin and Vimentin. In addition, the down‐regulation of α5‐nAChR or/and Stat3 reduced Jab1/Csn5 expression, while the silencing of α5‐nAChR or Jab1/Csn5 inhibited the migration and invasion of NSCLC cells. Mechanistically, α5‐nAChR contributes to EMT and metastasis by regulating Stat3‐Jab1/Csn5 signalling in NSCLC, suggesting that α5‐nAChR may be a potential target in NSCLC diagnosis and immunotherapy.

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“…EZH2, BMI1) are major drivers of stem cells, and a group of researchers from the University of Queensland have proposed BMI1 and EZH2 as prostate and oral CSC markers, respectively [89,91]. We have identified the novel role of PAF1/PD2 in the maintenance of ovarian and pancreatic CSCs, demonstrating that PAF1/PD2 interacts with Oct3/4 or PHF5A and maintains the stem cell features of ovarian/pancreatic CSCs [92–94]. It is also known that VEGF promotes stemness and has been shown as a breast CSC marker [95].…”

Section: Manifold Existence Of Cancer Stem Cells and Its Impact On Camentioning

confidence: 99%

Unraveling the journey of cancer stem cells from origin to metastasis

Nimmakayala

Batra

Ponnusamy

2019

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Cancer biology research over recent decades has given ample evidence for the existence of self-renewing and drug-resistant populations within heterogeneous tumors, widely recognized as cancer stem cells (CSCs). However, a lack of clear understanding about the origin, existence, maintenance, and metastatic roles of CSCs limit efforts towards the development of CSC-targeted therapy. In this review, we describe novel avenues of current CSC biology. In addition to cell fusion and horizontal gene transfer, CSCs are originated by mutations in somatic or differentiated cancer cells, resulting in de-differentiation and reprogramming. Recent studies also provided evidence for the existence of distinct or heterogeneous CSC populations within a single heterogeneous tumor. Our analysis of the literature also opens the doors for a novel hypothesis that CSC populations with specific phenotypes, metabolic profiles, and clonogenic potential metastasize to specific organs.

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Cigarette Smoke Induces Stem Cell Features of Pancreatic Cancer Cells via PAF1

Abstract: Exposure to cigarette smoke activates stem cell features of pancreatic cells, via CHRNA7 signaling and FOSL1 activation of PAF1 expression. Levels of PAF1 are increased in pancreatic tumors of humans and mice with chronic cigarette smoke exposure.

Cited by 75 publications

References 42 publications

Preclinical pharmacodynamic evaluation of a new Src/FOSL1 inhibitor, LY‐1816, in pancreatic ductal adenocarcinoma

Preclinical pharmacodynamic evaluation of a new Src/FOSL1 inhibitor, LY‐1816, in pancreatic ductal adenocarcinoma

α5‐nAChR contributes to epithelial‐mesenchymal transition and metastasis by regulating Jab1/Csn5 signalling in lung cancer

Unraveling the journey of cancer stem cells from origin to metastasis

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