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Growth Factor And Malignancy And Lkb1

Arnaud Jacquel, Frederic Luciano, Guillaume Robert, Patrick Auberger
AMP-activated protein kinase (AMPK) is a heterotrimeric serine/threonine kinase consisting of the arrangement of various α β, and γisoforms that are expressed differently depending on the tissue or the cell lineage. AMPK is one of the major sensors of energy status in mammalian cells and as such plays essential roles in the regulation of cellular homeostasis, metabolism, cell growth, differentiation, apoptosis, and autophagy. AMPK is activated by two upstream kinases, the tumor suppressor liver kinase B1 (LKB1) and the calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) through phosphorylation of the kinase on Thr172, leading to its activation...
September 30, 2018: International Journal of Molecular Sciences
Michael Troncone, Stephanie M Cargnelli, Linda A Villani, Naghmeh Isfahanian, Lindsay A Broadfield, Laura Zychla, Jim Wright, Gregory Pond, Gregory R Steinberg, Theodoros Tsakiridis
Lung cancer is the most fatal malignancy worldwide, in part, due to high resistance to cytotoxic therapy. There is need for effective chemo-radio-sensitizers in lung cancer. In recent years, we began to understand the modulation of metabolism in cancer and its importance in tumor progression and survival after cytotoxic therapy. The activity of biosynthetic pathways, driven by the Growth Factor Receptor/Ras/PI3k/Akt/mTOR pathway, is balanced by the energy stress sensor pathway of LKB1/AMPK/p53. AMPK responds both to metabolic and genotoxic stress...
August 22, 2017: Oncotarget
K M Biernacka, R A Persad, A Bahl, D Gillatt, J M P Holly, C M Perks
The incidence of many common cancers varies between different populations and appears to be affected by a Western lifestyle. Highly proliferative malignant cells require sufficient levels of nutrients for their anabolic activity. Therefore, targeting genes and pathways involved in metabolic pathways could yield future therapeutics. A common pathway implicated in energetic and nutritional requirements of a cell is the LKB1/AMPK pathway. Metformin is a widely studied anti-diabetic drug, which improves glycaemia in patients with type 2 diabetes by targeting this pathway...
January 2017: Endocrine-related Cancer
Angiolo Gadducci, Nicoletta Biglia, Roberta Tana, Stefania Cosio, Martina Gallo
Metformin exerts antitumor effects mainly through AMP-activated protein kinase [AMPK] activation and phosphatidylinositol 3-kinase [PI3K]-Akt-mammalian target of rapamycin [mTOR] inhibition. This drug leads to activation of the cellular energy-sensing liver kinase B1 [LKB1]/AMPK pathway. LKB1 is implicated as a tumor suppressor gene in molecular pathogenesis of different malignancies. AMPK is a serine/threonine protein kinase that acts as an ultra-sensitive cellular energy sensor maintaining the energy balance within the cell...
September 2016: Critical Reviews in Oncology/hematology
Giulia Santinon, Arianna Pocaterra, Sirio Dupont
Metabolism is a fundamental cellular function that can be reprogrammed by signaling pathways and oncogenes to meet cellular requirements. An emerging paradigm is that signaling and transcriptional networks can be in turn regulated by metabolism, allowing cells to coordinate their metabolism and behavior in an integrated manner. The activity of the YAP/TAZ transcriptional coactivators, downstream transducers of the Hippo cascade and powerful pro-oncogenic factors, was recently found to be regulated by metabolic pathways, such as aerobic glycolysis and mevalonate synthesis, and by the nutrient-sensing LKB1-AMPK and TSC-mTOR pathways...
April 2016: Trends in Cell Biology
Imoh S Okon, Ye Ding, Kathleen A Coughlan, Qiongxin Wang, Ping Song, Doris M Benbrook, Ming-Hui Zou
Neuropilin-1 (NRP-1) has emerged as an important driver of tumor-promoting phenotypes of human malignancies. However, incomplete knowledge exists as to how this single-pass transmembrane receptor mediates pleiotropic tumor-promoting functions. The purpose of this study was to evaluate NRP-1 expression and metastatic properties in 94 endometrial cancer and matching serum specimens and in a lung cancer cell line. We found that NRP-1 expression significantly correlated with increased tumoral expression of vascular endothelial growth factor 2 (VEGFR2) and serum levels of hepatocyte growth factor (HGF) and cell growth-stimulating factor (C-GSF)...
February 16, 2016: Oncotarget
Cheng-Yi Chang, Jian-Ri Li, Chih-Cheng Wu, Yen-Chuan Ou, Wen-Ying Chen, Yu-Hsiang Kuan, Wen-Yi Wang, Chun-Jung Chen
Autophagy and apoptosis represent important cellular processes involved in cancer cell killing mechanisms. Epidermal growth factor receptor inhibitor gefitinib and valproic acid have been implicated in the treatment of malignancies including glioma involving autophagic and apoptotic mechanisms. Therefore, it is interesting to investigate whether a combination of gefitinib and valproic acid shows better cancer cell killing effect on human glioma cells. We found that a nontoxic concentration of valproic acid sensitized U87 and T98G glioma cells to gefitinib cytotoxicity by inhibiting cell growth and long-term clonogenic survival...
November 2015: IUBMB Life
Takeshi Shimamura, Zhao Chen, Margaret Soucheray, Julian Carretero, Eiki Kikuchi, Jeremy H Tchaicha, Yandi Gao, Katherine A Cheng, Travis J Cohoon, Jun Qi, Esra Akbay, Alec C Kimmelman, Andrew L Kung, James E Bradner, Kwok-Kin Wong
PURPOSE: Amplification of MYC is one of the most common genetic alterations in lung cancer, contributing to a myriad of phenotypes associated with growth, invasion, and drug resistance. Murine genetics has established both the centrality of somatic alterations of Kras in lung cancer, as well as the dependency of mutant Kras tumors on MYC function. Unfortunately, drug-like small-molecule inhibitors of KRAS and MYC have yet to be realized. The recent discovery, in hematologic malignancies, that bromodomain and extra-terminal (BET) bromodomain inhibition impairs MYC expression and MYC transcriptional function established the rationale of targeting KRAS-driven non-small cell lung cancer (NSCLC) with BET inhibition...
November 15, 2013: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
L-H Tsai, P-M Chen, Y-W Cheng, C-Y Chen, G-T Sheu, T-C Wu, H Lee
LKB1 loss is a frequent homozygous deletion and/or gene mutation found in lung adenocarcinomas. However, few cases of LKB1 loss by either deletion or mutation are seen in Asian patients. Our preliminary data showed that LKB1 loss was associated with p53 mutation in lung tumors from Taiwanese adenocarcinoma patients and p53 transcription is directly regulated by NKX2-1. Therefore, we hypothesized that LKB1 loss could occur due to aberration of p53 regulation mediated by NKX2-1. In the present study, 16 lung adenocarcinoma cell lines were investigated to determine if LKB1 transcription could be deregulated by NKX2-1-mediated p53 aberration...
July 17, 2014: Oncogene
Zhigang Zhuang, Kai Wang, Xiaolin Cheng, Xueying Qu, Beiqi Jiang, Zhengdong Li, Jianming Luo, Zhiming Shao, Tao Duan
Constitutive activation of the Hedgehog (Hh) signaling pathway has been implicated in the development of many human malignancies. Hh targets, such as Patched (PTCH), smoothened (SMO), Sonic hedgehog (SHH) and glioma-associated oncogene homologue 1 (GLI1), are markers of Hh signaling activation and expressed in most Hh-associated tumors. The protein kinase LKB1 has been shown to slow proliferation and induce cell-cycle arrest in many cell lines. In this study, we observed that activated LKB1 decreased the expression of factors related to Hh reporter activity in MDA-MB-231 breast cancer cells, including of SMO, SHH and GLI1...
2013: PloS One
Susanne E Korsse, Katharina Biermann, G Johan A Offerhaus, Anja Wagner, Evelien Dekker, Elisabeth M H Mathus-Vliegen, Ernst J Kuipers, Monique E van Leerdam, Wendy van Veelen
Peutz-Jeghers syndrome (PJS) is caused by mutations in the LKB1 gene. It is characterized by gastrointestinal polyposis and an increased cancer risk, mainly in the gastrointestinal tract. Mechanisms of PJS-associated carcinogenesis are unclear. We investigated the involvement of candidate genes and molecular pathways in PJS-associated gastrointestinal cancers and dysplastic hamartomas. Cases were selected from the Dutch PJS cohort. Available tissue was immunostained for phospho-S6, β-catenin, P53 and SMAD4...
July 2013: Carcinogenesis
Nastaran M Ghahhari, Hamed M Ghahhari, Mehdi Kadivar
BACKGROUND: Salivary gland tumors (SGTs) are known for their specific heterogeneity and ambiguous outcome for the affected patients. The LKB1 and SMAD4 genes are pivotal components of important signaling pathways, including AMPK and TGF-β. To our knowledge, no study has reported an association between the expression levels of these genes in SGTs. The expression levels of LKB1 and SMAD4 were evaluated to clarify their possible crosstalk in SGTs. MATERIALS AND METHODS: A total of 50 fresh tissue specimens were obtained from patients with SGTs, including pleomorphic adenoma (PA), Warthin's tumor (WT), intermediate grade mucoepidermoid carcinoma (MEC), salivary duct carcinoma (SDC), and carcinoma ex pleomorphic adenoma (CexPA), as well as 8 normal samples...
2012: Onkologie
Hyun-Seuk Moon, Xiaowen Liu, Jutta M Nagel, John P Chamberland, Kalliope N Diakopoulos, Mary T Brinkoetter, Maria Hatziapostolou, Yan Wu, Simon C Robson, Dimitrios Iliopoulos, Christos S Mantzoros
BACKGROUND: Obesity and a high-fat diet are associated with the risk and progression of colon cancer. Low adiponectin levels may play an important role in the development of colon and other obesity-related malignancies. No previous studies have directly investigated the mechanistic effects of adiponectin on colon cancer in the settings of obesity, a high-fat diet and/or adiponectin deficiency. OBJECTIVE: To investigate the effects of adiponectin on the growth of colorectal cancer in adiponectin-deficient or wild-type-C57BL/6 mice fed a low-fat or high-fat diet...
April 2013: Gut
Y Gu, S Lin, J-L Li, H Nakagawa, Z Chen, B Jin, L Tian, D A Ucar, H Shen, J Lu, S N Hochwald, F J Kaye, L Wu
LKB1 is a tumor susceptibility gene for the Peutz-Jeghers cancer syndrome and is a target for mutational inactivation in sporadic human malignancies. LKB1 encodes a serine/threonine kinase that has critical roles in cell growth, polarity and metabolism. A novel and important function of LKB1 is its ability to regulate the phosphorylation of CREB-regulated transcription co-activators (CRTCs) whose aberrant activation is linked with oncogenic activities. However, the roles and mechanisms of LKB1 and CRTC in the pathogenesis of esophageal cancer have not been previously investigated...
January 26, 2012: Oncogene
T Komiya, A Coxon, Y Park, W-D Chen, M Zajac-Kaye, P Meltzer, T Karpova, F J Kaye
Activation of Crtc1 (also known as Mect1/Torc1) by a t(11;19) chromosomal rearrangement underlies the etiology of malignant salivary gland tumors. As LKB1 is a target for mutational inactivation in lung cancer and was recently shown to regulate hepatic Crtc2/CREB transcriptional activity in mice, we now present evidence suggesting disruption of an LKB1/Crtc pathway in cancer. Although Crtc1 is preferentially expressed in adult brain tissues, we observed elevated levels of steady-state Crtc1 in thoracic tumors...
March 18, 2010: Oncogene
Xuan Liang, Ke-Jun Nan, Chun-Li Li, Yu Yao, Tao Tian, Shu-Hong Wang
AIM: To determine the effects of exogenous LKB1 gene on biological behavior of lung carcinoma cells. METHODS: Nest PCR was used to clone LKB1 gene pcDNA-LKB1 and pcDNA3.1 were introduced into A549 cell line by lipofectin transfection, and the A549 cells stably expressing LKB1 gene were established by G418 selection. The expression of LKB1 and STAT3 protein was detected by Western blot. Cell proliferation was observed by growth curve and clone formation. Cell cycle and apoptosis were assayed by flow cytometry(FCM)...
December 2008: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
Dong Wook Kim, Hyo Kyun Chung, Ki Cheol Park, Jung Hwan Hwang, Young Suk Jo, Jongkyeong Chung, Dhananjaya V Kalvakolanu, Nicoletta Resta, Minho Shong
The tumor suppressor LKB1 (STK11) is a cytoplasmic/nuclear serine/threonine kinase, defects in which cause Peutz-Jeghers syndrome (PJS) in humans and animals. Recent studies showed that loss of function of LKB1 is associated with sporadic forms of lung, pancreatic, and ovarian cancer. In cancer cells, LKB1 is inactivated by two mechanisms: mutations in its central kinase domain or complete loss of LKB1 expression. Inactivation of LKB1 is associated with progression of PJS and transformation of benign polyps into malignant tumors...
December 2007: Molecular Endocrinology
Julia Nafz, Johanna De-Castro Arce, Verena Fleig, Andrea Patzelt, Sybille Mazurek, Frank Rösl
Carcinogenesis is a dynamic and stepwise process, which is accompanied by a variety of somatic and epigenetic alterations in response to a changing microenvironment. Hypoxic conditions will select for cells that have adjusted their metabolic profile and can maintain proliferation by successfully competing for scarce nutritional and oxygen resources. In the present study we have investigated the effects of energy depletion in the context of HPV (human papillomavirus)-induced pathogenesis. We show that cervical carcinoma cell lines are susceptible to undergoing either growth arrest or cell death under conditions of metabolic stress induced by AICAR (5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside), a known activator of the AMPK (AMP-activated protein kinase)...
May 1, 2007: Biochemical Journal
Hiroyuki Motoshima, Barry J Goldstein, Motoyuki Igata, Eiichi Araki
AMPK is a serine/threonine protein kinase, which serves as an energy sensor in all eukaryotic cell types. Published studies indicate that AMPK activation strongly suppresses cell proliferation in non-malignant cells as well as in tumour cells. These actions of AMPK appear to be mediated through multiple mechanisms including regulation of the cell cycle and inhibition of protein synthesis, de novo fatty acid synthesis, specifically the generation of mevalonate as well as other products downstream of mevalonate in the cholesterol synthesis pathway...
July 1, 2006: Journal of Physiology
Baldwin C Mak, Raymond S Yeung
The study of hereditary tumor syndromes has laid a solid foundation toward understanding the genetic basis of cancer. One of the latest examples comes from the study of tuberous sclerosis complex (TSC). As a member of the phakomatoses, TSC is characterized by the appearance of benign tumors, most notably in the central nervous system, kidney, heart, lung, and skin. While classically described as "hamartomas," the pathology of the lesions has features suggestive of abnormal cellular proliferation, size, differentiation, and migration...
2004: Cancer Investigation
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