DLC-1 suppresses non-small cell lung cancer growth and invasion by RhoGAP-dependent and independent mechanisms.

Abstract:

:Expression of the tumor suppressor deleted in liver cancer-1 (DLC-1) is lost in non-small cell lung (NSCLC) and other human carcinomas, and ectopic DLC-1 expression dramatically reduces proliferation and tumorigenicity. DLC-1 is a multi-domain protein that includes a Rho GTPase activating protein (RhoGAP) domain which has been hypothesized to be the basis of its tumor suppressive actions. To address the importance of the RhoGAP function of DLC-1 in tumor suppression, we performed biochemical and biological studies evaluating DLC-1 in NSCLC. Full-length DLC-1 exhibited strong GAP activity for RhoA as well as RhoB and RhoC, but only very limited activity for Cdc42 in vitro. In contrast, the isolated RhoGAP domain showed 5- to 20-fold enhanced activity for RhoA, RhoB, RhoC, and Cdc42. DLC-1 protein expression was absent in six of nine NSCLC cell lines. Restoration of DLC-1 expression in DLC-1-deficient NSCLC cell lines reduced RhoA activity, and experiments with a RhoA biosensor demonstrated that DLC-1 dramatically reduces RhoA activity at the leading edge of cellular protrusions. Furthermore, DLC-1 expression in NSCLC cell lines impaired both anchorage-dependent and -independent growth, as well as invasion in vitro. Surprisingly, we found that the anti-tumor activity of DLC-1 was due to both RhoGAP-dependent and -independent activities. Unlike the rat homologue p122RhoGAP, DLC-1 was not capable of activating the phospholipid hydrolysis activity of phospholipase C-delta1. Combined, these studies provide information on the mechanism of DLC-1 function and regulation, and further support the role of DLC-1 tumor suppression in NSCLC.

journal_name

Mol Carcinog

journal_title

Molecular carcinogenesis

authors

Healy KD,Hodgson L,Kim TY,Shutes A,Maddileti S,Juliano RL,Hahn KM,Harden TK,Bang YJ,Der CJ

doi

10.1002/mc.20389

subject

Has Abstract

pub_date

2008-05-01 00:00:00

pages

326-37

issue

5

eissn

0899-1987

issn

1098-2744

journal_volume

47

pub_type

杂志文章
  • Homozygous K5Cre transgenic mice have wavy hair and accelerated malignant progression in a murine model of skin carcinogenesis.

    abstract::Mice with conditional gene deletions have been extremely valuable in allowing investigators to study the genes of interest in a tissue-specific manner. The Cre-loxP recombination system provides a powerful tool to produce targeted rearrangements of particular genes. The keratin 5-Cre recombinase (K5Cre) transgenic mou...

    journal_title:Molecular carcinogenesis

    pub_type: 杂志文章

    doi:10.1002/mc.20192

    authors: Chan EL,Peace BE,Toney K,Kader SA,Pathrose P,Collins MH,Waltz SE

    更新日期:2007-01-01 00:00:00

  • Upstream stimulatory factor (USF) as a transcriptional suppressor of human telomerase reverse transcriptase (hTERT) in oral cancer cells.

    abstract::Telomerase activity is suppressed in normal human somatic tissues but is activated in cancer cells and immortal cell lines. The reverse transcriptase (RT) subunit human telomerase reverse transcriptase (hTERT) is the key regulator of telomerase activity. The hTERT promoter contains E-box elements and may allow upstrea...

    journal_title:Molecular carcinogenesis

    pub_type: 杂志文章

    doi:10.1002/mc.20129

    authors: Chang JT,Yang HT,Wang TC,Cheng AJ

    更新日期:2005-11-01 00:00:00

  • Accelerated onset of uterine tumors in transgenic mice with aberrant expression of the estrogen receptor after neonatal exposure to diethylstilbestrol.

    abstract::The role of estrogen and the estrogen receptor (ER) in the induction and promotion of tumors was investigated by using transgenic MT-mER mice, which overexpress the ER. It was hypothesized that because of this abnormal expression of the ER, the reproductive-tract tissues of the MT-mER mice may be more susceptible to t...

    journal_title:Molecular carcinogenesis

    pub_type: 杂志文章

    doi:10.1002/(sici)1098-2744(199708)19:4<236::aid-mc4>3

    authors: Couse JF,Davis VL,Hanson RB,Jefferson WN,McLachlan JA,Bullock BC,Newbold RR,Korach KS

    更新日期:1997-08-01 00:00:00

  • A human endonuclease incises ultraviolet-irradiated DNA at cytosines and oxidized DNA at thymines.

    abstract::Both ultraviolet irradiation and oxidation of DNA produce a variety of pyrimidine base damages. A human endonuclease recognizes such altered bases on these DNA substrates. This human endonuclease incises ultraviolet-irradiated DNA exclusively at sites of photochemically modified cytosines. The precise sites of incisio...

    journal_title:Molecular carcinogenesis

    pub_type: 杂志文章

    doi:10.1002/mc.2940020404

    authors: Gallagher PE,Weiss RB,Brent TP,Duker NJ

    更新日期:1989-01-01 00:00:00

  • Transforming growth factor-beta responsiveness in DPC4/SMAD4-null cancer cells.

    abstract::DPC4/SMAD4 is a candidate tumor suppressor gene with a strikingly high frequency of gene alterations in pancreatic cancer that suggests a discrete role for DPC4 in these tumors. DPC4 tumor-suppressive function has been implicated to mediate the transforming growth factor-beta (TGFbeta)-suppressive pathway; however, in...

    journal_title:Molecular carcinogenesis

    pub_type: 杂志文章

    doi:10.1002/(sici)1098-2744(199909)26:1<37::aid-mc5>3.

    authors: Dai JL,Schutte M,Bansal RK,Wilentz RE,Sugar AY,Kern SE

    更新日期:1999-09-01 00:00:00

  • No involvement of Ki-ras or p53 gene mutations in colitis-associated rat colon tumors induced by 1-hydroxyanthraquinone and methylazoxymethanol acetate.

    abstract::1-Hydroxyanthraquinone (1-HA), which is present in some herbs, and methylazoxymethanol (MAM) acetate, a metabolite of azoxymethane, show synergistic carcinogenicity in rat colon, and 1-HA induces ulcerative changes with simultaneous severe inflammation of the entire colon. In this study, mutations in Ki-ras (exons 1 a...

    journal_title:Molecular carcinogenesis

    pub_type: 杂志文章

    doi:10.1002/mc.2940120403

    authors: Suzui M,Yoshimi N,Ushijima T,Hirose Y,Makita H,Wang A,Kawamori T,Tanaka T,Mori H,Nagao M

    更新日期:1995-04-01 00:00:00

  • Grb2-associated binder 1 (Gab1) genetic polymorphism, Helicobacter pylori infection, and chronic atrophic gastritis among older adults from Germany.

    abstract::Grb2-associated binder 1 (Gab1) plays an important role in the regulation of cell growth and transformation. A single nucleotide polymorphism (SNP) (rs3805246) in the Gab1 gene has been suggested to be related to the risk of Helicobacter pylori infection and chronic atrophic gastritis (CAG) in a study from Japan. We a...

    journal_title:Molecular carcinogenesis

    pub_type: 杂志文章

    doi:10.1002/mc.20662

    authors: Gao L,Weck MN,Nieters A,Brenner H

    更新日期:2010-10-01 00:00:00

  • Epigenetic analysis of microRNA genes in tumors from surgically resected lung cancer patients and association with survival.

    abstract::Aberrant microRNA (miRNA) expression is involved in tumorigenesis of several cancers, including non-small cell lung cancer (NSCLC). Furthermore, expression of some miRNAs has been shown to be under epigenetic regulation. However, less is known regarding the role of miRNA methylation in NSCLC development or clinical ou...

    journal_title:Molecular carcinogenesis

    pub_type: 杂志文章

    doi:10.1002/mc.22149

    authors: Tan W,Gu J,Huang M,Wu X,Hildebrandt MA

    更新日期:2015-06-01 00:00:00

  • Association of expression quantitative trait loci for long noncoding RNAs with lung cancer risk in Asians.

    abstract::Identification of long noncoding RNA (lncRNA) expression quantitative trait loci (lncR-eQTL) that associated with lung cancer can provide insights into regulatory mechanisms of lncRNA, and help reveal the role of lncRNA in lung cancer. A two-stage case-control design was implemented in this study. We first selected th...

    journal_title:Molecular carcinogenesis

    pub_type: 杂志文章

    doi:10.1002/mc.23013

    authors: Sun Q,Wang Y,Fan J,Li Z,Zhang J,Wang L,Fan X,Ji M,Zhu M,Dai J,Ma H,Jin G,Hu Z,Shen H

    更新日期:2019-07-01 00:00:00

  • Cinnamon extract reduces VEGF expression via suppressing HIF-1α gene expression and inhibits tumor growth in mice.

    abstract::Although many anti-VEGF agents are available for cancer treatment, side effects of these agents limit their application for cancer treatment and prevention. Here we studied the potential use of a diet-based agent as an inhibitor for VEGF production. Using a VEGF reporter assay, our data showed that an extract from cin...

    journal_title:Molecular carcinogenesis

    pub_type: 杂志文章

    doi:10.1002/mc.22506

    authors: Zhang K,Han ES,Dellinger TH,Lu J,Nam S,Anderson RA,Yim JH,Wen W

    更新日期:2017-02-01 00:00:00

  • CD44/cellular prion protein interact in multidrug resistant breast cancer cells and correlate with responses to neoadjuvant chemotherapy in breast cancer patients.

    abstract::Multidrug resistance (MDR) is one of the most important factors leading to chemotherapeutic failure in patients with breast cancer. The invasive/metastatic ability of MDR cells is strengthened compared with their parental cells. However, the mechanisms underlying MDR have not been fully elucidated. We found that CD44 ...

    journal_title:Molecular carcinogenesis

    pub_type: 杂志文章

    doi:10.1002/mc.22021

    authors: Cheng Y,Tao L,Xu J,Li Q,Yu J,Jin Y,Chen Q,Xu Z,Zou Q,Liu X

    更新日期:2014-09-01 00:00:00

  • Oncogene RNA helicase DDX6 promotes the process of c-Myc expression in gastric cancer cells.

    abstract::Human DEAD-box RNA helicase gene DDX6 was cloned from B-cell lymphoma cell line RC-K8. Previously, we reported that DDX6 acts as oncogene in several cancers such as colorectal cancer and hepatocellular carcinoma. However, the detailed mechanism of DDX6 action in carcinogenesis is largely unknown. In this study, we exa...

    journal_title:Molecular carcinogenesis

    pub_type: 杂志文章

    doi:10.1002/mc.22781

    authors: Taniguchi K,Iwatsuki A,Sugito N,Shinohara H,Kuranaga Y,Oshikawa Y,Tajirika T,Futamura M,Yoshida K,Uchiyama K,Akao Y

    更新日期:2018-05-01 00:00:00

  • Growth factor-independent proliferation of rat mammary carcinoma cells by autocrine secretion of neu-differentiation factor/heregulin and transforming growth factor-alpha.

    abstract::Serially transplantable rat mammary tumor (RMT) cells are not dependent on exogenous epidermal growth factor (EGF) and insulin-like growth factor-I for continuous growth in serum-free medium. Previously, we found that conditioned medium obtained from these cells contained EGF-like mitogenic activity and stimulated tyr...

    journal_title:Molecular carcinogenesis

    pub_type: 杂志文章

    doi:10.1002/(SICI)1098-2744(199602)15:2<134::AID-MC6>3

    authors: Ethier SP,Langton BC,Dilts CA

    更新日期:1996-02-01 00:00:00

  • Gene expression changes associated with chemically induced rat mammary carcinogenesis.

    abstract::Experimentally induced models of breast carcinogenesis in the rat are widely used for studying the biology of breast cancer and for developing and evaluating cancer prevention and control strategies. However, very little is known about gene expression changes that are associated with experimentally induced mammary car...

    journal_title:Molecular carcinogenesis

    pub_type: 杂志文章

    doi:10.1002/(sici)1098-2744(199710)20:2<204::aid-mc7>3

    authors: Lu J,Pei H,Kaeck M,Thompson HJ

    更新日期:1997-10-01 00:00:00

  • Microsatellite instability and loss of heterozygosity on chromosome 10 in rat mammary tumors induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine.

    abstract::Microsatellite instability (MI) and loss of heterozygosity (LOH) were examined in mammary tumors induced in Sprague-Dawley x F344 F1 female rats by 2-amino-l-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Examination of 62 microsatellite loci revealed MI in nine of 15 (60%) PhIP-induced mammary tumors, and five of thes...

    journal_title:Molecular carcinogenesis

    pub_type: 杂志文章

    doi:10.1002/(SICI)1098-2744(199603)15:3<176::AID-MC3>3

    authors: Toyota M,Ushijima T,Weisburger JH,Hosoya Y,Canzian F,Rivenson A,Imai K,Sugimura T,Nagao M

    更新日期:1996-03-01 00:00:00

  • Magnolin targeting of ERK1/2 inhibits cell proliferation and colony growth by induction of cellular senescence in ovarian cancer cells.

    abstract::Ras/Raf/MEKs/ERKs and PI3 K/Akt/mTOR signaling pathways have key roles in cancer development and growth processes, as well as in cancer malignance and chemoresistance. In this study, we screened the therapeutic potential of magnolin using 15 human cancer cell lines and combined magnolin sensitivity with the CCLE mutao...

    journal_title:Molecular carcinogenesis

    pub_type: 杂志文章

    doi:10.1002/mc.22909

    authors: Song JH,Lee CJ,An HJ,Yoo SM,Kang HC,Lee JY,Kim KD,Kim DJ,Lee HS,Cho YY

    更新日期:2019-01-01 00:00:00

  • Expression level of miR-34a rather than P53 gene status correlates with mutability in related human lymphoblast cell lines.

    abstract::The P53 gene is a tumor suppressor gene and can prevent mutation and tumor induction though apoptosis and DNA repair when it is activated by genotoxic stress. miR-34a expression is regulated by the P53 gene and might be required for cell response to DNA damage. TK6 cells are human lymphoblast cells with normal P53 fun...

    journal_title:Molecular carcinogenesis

    pub_type: 杂志文章

    doi:10.1002/mc.20830

    authors: Chen X,Yan J,Chen T

    更新日期:2012-08-01 00:00:00

  • Frequency of Ki-ras mutations and DNA alkylation in colorectal tissue from individuals living in Manchester.

    abstract::Most human colorectal cancers arise through the accumulation of a series of genetic alterations such as point mutations within the Ki-ras and p53 genes, but the chemical carcinogens that may be implicated in these events are still unidentified. In a previous study, we showed that DNA from human colorectal tissue conta...

    journal_title:Molecular carcinogenesis

    pub_type: 杂志文章

    doi:10.1002/(SICI)1098-2744(199605)16:1<12::AID-MC3>3.

    authors: Jackson PE,Hall CN,Badawi AF,O'Connor PJ,Cooper DP,Povey AC

    更新日期:1996-05-01 00:00:00

  • 2-methoxyestradiol blocks cell-cycle progression at G(2)/M phase and inhibits growth of human prostate cancer cells.

    abstract::2-Methoxyestradiol (2-ME), an endogenous metabolite of 17beta-estradiol, is present in human blood and urine. Here we show for the first time that 2-ME significantly inhibited the growth of normal prostate epithelial cells and androgen-dependent LNCaP and androgen-independent DU145 prostate cancer cells. This growth i...

    journal_title:Molecular carcinogenesis

    pub_type: 杂志文章

    doi:10.1002/mc.1046

    authors: Kumar AP,Garcia GE,Slaga TJ

    更新日期:2001-07-01 00:00:00

  • Activation and up-regulation of translation initiation factor 4B contribute to arsenic-induced transformation.

    abstract::Arsenic is a known human carcinogen. However, the mechanism of how arsenic induces cell transformation remains unclear. In this study, we demonstrated that long-term exposure to sodium arsenite at low-dose (2 µM) increases cell proliferation and neoplastic transformation in a mouse epidermal cell model, JB6 promotion-...

    journal_title:Molecular carcinogenesis

    pub_type: 杂志文章

    doi:10.1002/mc.20733

    authors: Zhang Y,Wang Q,Guo X,Miller R,Guo Y,Yang HS

    更新日期:2011-07-01 00:00:00

  • Differential expression of p16(INK4a) in azoxymethane-induced mouse colon tumorigenesis.

    abstract::Alterations in the p16(INK4a) gene have been implicated in the pathogenesis of different human cancers and animal tumors. We postulated that alterations in the p16(INK4a) gene may also be involved in mouse colon tumorigenesis induced by the chemical carcinogen azoxymethane (AOM). In the present study, p16(INK4a) delet...

    journal_title:Molecular carcinogenesis

    pub_type: 杂志文章

    doi:10.1002/1098-2744(200007)28:3<139::aid-mc2>3.0.co;

    authors: Wang QS,Papanikolaou A,Nambiar PR,Rosenberg DW

    更新日期:2000-07-01 00:00:00

  • Potent cell growth inhibitory effects in hepatitis B virus X protein positive hepatocellular carcinoma cells by the selective cyclooxygenase-2 inhibitor celecoxib.

    abstract::Hepatitis B virus (HBV) X protein (HBx) and cyclooxygenase-2 (COX-2) are all playing roles in hepatocellular carcinoma (HCC), but the reversing effects of COX-2 inhibitors on the neoplastic features caused by HBx protein is still unclear. To further evaluate the therapeutic potential of celecoxib on HBx mediated trans...

    journal_title:Molecular carcinogenesis

    pub_type: 杂志文章

    doi:10.1002/mc.20455

    authors: Xie H,Gao L,Chai N,Song J,Wang J,Song Z,Chen C,Pan Y,Zhao L,Sun S,Wu K,Feitelson MA,Liu J,Fan D

    更新日期:2009-01-01 00:00:00

  • Association between TP53 gene ARG72PRO polymorphism and chromosome aberrations in human cancers.

    abstract::It is well known that the TP53 gene considerably influences on DNA repair processes. Polymorphisms in the TP53 gene, particularly the well-known Arg72Pro in codon 72 of exon 4 (Ex4+119 G>C; rs1042522), can modify the functionality of the p53 protein and activation of DNA repair. Actually, polymorphic variants Arg and ...

    journal_title:Molecular carcinogenesis

    pub_type: 杂志文章

    doi:10.1002/mc.20633

    authors: Litviakov NV,Denisov EV,Takhauov RM,Karpov AB,Skobel'skaja EV,Vasil'eva EO,Goncharik OO,Ageeva AM,Mamonova NV,Mezheritskiy SA,Sevost'janova NV,Koshel AP

    更新日期:2010-06-01 00:00:00

  • Species-specific effects of the hepatocarcinogens 3'-methyl-4-dimethyl-aminoazobenzene and ortho-aminoazotoluene in mouse and rat liver.

    abstract::The effects of rat-specific hepatocarcinogen 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB), mouse-specific hepatocarcinogen ortho-aminoazotoluene (OAT), non-species-specific hepatocarcinogen diethylnitrosamine (DENA), and non-carcinogenic 4'-methyl-4-dimethylaminoazobenzene (4'-MeDAB) on glucocorticoid induction of t...

    journal_title:Molecular carcinogenesis

    pub_type: 杂志文章

    doi:10.1002/mc.20090

    authors: Merkulova TI,Kropachev KY,Timofeeva OA,Vasiliev GV,Levashova ZB,Ilnitskaya SI,Kobzev VF,Pakharukova MY,Bryzgalov LO,Kaledin VI

    更新日期:2005-12-01 00:00:00

  • Differential expression of cytokines in rat osteosarcoma and malignant fibrous histiocytoma cell lines induced by 4-(hydroxyamino)quinoline-1-oxide.

    abstract::Cytokines are considered to play an important role in tumor pathogenesis and progression, and recent studies have demonstrated that a variety of forms, including interleukins (ILs) and transforming growth factor-beta(s) (TGF-beta(s)), may regulate tumors. In the present study, the expression of TGF-beta isoforms and I...

    journal_title:Molecular carcinogenesis

    pub_type: 杂志文章

    doi:

    authors: Honoki K,Tsujiuchi T,Sasaki Y,Tsutsumi M,Morishita T,Kido A,Miyauchi Y,Mii Y,Takakura Y,Konishi Y

    更新日期:2002-02-01 00:00:00

  • Overexpression of Evi-1 oncoprotein represses TGF-β signaling in colorectal cancer.

    abstract::Human colorectal cancer (CRC) cells are resistant to the anti-proliferative effect of transforming growth factor-β (TGF-β), suggesting that disruption of TGF-β signaling plays an important role in colorectal carcinogenesis. Ecotropic virus integration site-1 (Evi-1) oncoprotein represses TGF-β signaling by interacting...

    journal_title:Molecular carcinogenesis

    pub_type: 杂志文章

    doi:10.1002/mc.21852

    authors: Deng X,Cao Y,Liu Y,Li F,Sambandam K,Rajaraman S,Perkins AS,Fields AP,Hellmich MR,Townsend CM Jr,Thompson EA,Ko TC

    更新日期:2013-04-01 00:00:00

  • Triptolide sensitizes breast cancer cells to Doxorubicin through the DNA damage response inhibition.

    abstract::Triptolide is an active component from a Chinese herb, Tripterygium wilfordii which has been applied for treating immune-related diseases over centuries. Recently, it was reported that a variety of cancer cell lines could be sensitized to DNA-damage based chemotherapy drugs in combination with Triptolide treatment. In...

    journal_title:Molecular carcinogenesis

    pub_type: 杂志文章

    doi:10.1002/mc.22795

    authors: Deng Y,Li F,He P,Yang Y,Yang J,Zhang Y,Liu J,Tong Y,Li Q,Mei X,Shu Z,Zhao Q

    更新日期:2018-06-01 00:00:00

  • Phenylbutyl isoselenocyanate induces reactive oxygen species to inhibit androgen receptor and to initiate p53-mediated apoptosis in LNCaP prostate cancer cells.

    abstract::Previous studies have established the in vivo bioavailability and efficacious dosages of phenylbutyl isoselenocyanate (ISC-4), a selenium-substituted isothiocyanate, against mouse xenograft models of human melanoma and colorectal cancer. To explore its potential attributes against prostate cancer, we treated human LNC...

    journal_title:Molecular carcinogenesis

    pub_type: 杂志文章

    doi:10.1002/mc.22825

    authors: Wu W,Karelia D,Pramanik K,Amin SG,Sharma AK,Jiang C,Lu J

    更新日期:2018-08-01 00:00:00

  • p53 gene mutations in human endometrial carcinoma.

    abstract::Although carcinoma of the uterine endometrium is the most frequently diagnosed malignancy of the female reproductive tract, the molecular genetic features of this tumor have yet to be described in significant detail. Since mutations of the p53 tumor suppressor gene are the single most common genetic alteration found i...

    journal_title:Molecular carcinogenesis

    pub_type: 杂志文章

    doi:10.1002/mc.2940050403

    authors: Risinger JI,Dent GA,Ignar-Trowbridge D,McLachlan JA,Tsao MS,Senterman M,Boyd J

    更新日期:1992-01-01 00:00:00

  • Sequence context-specific mutagenesis and base excision repair.

    abstract::Base excision repair (BER) is critical for the maintenance of genome stability because it repairs at least 20,000 endogenously generated DNA lesions/cell/d. Several enzymes within the BER pathway exhibit sequence context dependency during the excision and DNA synthesis steps of repair. New evidence is emerging that ge...

    journal_title:Molecular carcinogenesis

    pub_type: 杂志文章,评审

    doi:10.1002/mc.20497

    authors: Donigan KA,Sweasy JB

    更新日期:2009-04-01 00:00:00