Integrative Genomic and Proteomic Analyses Identify Targets for Lkb1-Deficient Metastatic Lung Tumors

Carretero, Julián; Shimamura, Takeshi; Rikova, Klarisa; Jackson, Autumn L.; Wilkerson, Matthew D.; Borgman, Christa L.; Buttarazzi, Matthew S.; Sanofsky, Benjamin; McNamara, Kate; Brandstetter, K; Walton, Zandra E.; Gu, Ting; Silva, Jeffrey C.; Crosby, Katherine; Shapiro, Geoffrey I.; Maira, Sauveur Michel; Ji, Hongbin; Castrillón, Diego H.; Kim, Carla F.; García‐Echeverría, Carlos; Bardeesy, Nabeel; Sharpless, Norman E.; Hayes, D. Neil; Kim, William Y.; Engelman, Jeffrey A.; Wong, Kwok-Kin

doi:10.1016/j.ccr.2010.04.026

Cited by 216 publications

(260 citation statements)

References 43 publications

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“…IPMK, an upstream kinase in the inositol polyphosphate synthesis pathway, influences LKB1 activity in a catalytic activity-dependent manner (32), suggesting that higher inositol phosphates regulate LKB1. LKB1 has been reported to suppress FAK activity-dependent migration/invasion and metastasis (16,33,34), as well as to enhance E-cadherin levels (17,19). Using MCF7 and H1299 cells with LKB1 depletion, we confirm that LKB1 down-regulates cell spreading (Fig.…”

Section: Significancesupporting

confidence: 70%

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Inositol pyrophosphates promote tumor growth and metastasis by antagonizing liver kinase B1

Rao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The inositol pyrophosphates, molecular messengers containing an energetic pyrophosphate bond, impact a wide range of biologic processes. They are generated primarily by a family of three inositol hexakisphosphate kinases (IP6Ks), the principal product of which is diphosphoinositol pentakisphosphate (IP7). We report that IP6K2, via IP7 synthesis, is a major mediator of cancer cell migration and tumor metastasis in cell culture and in intact mice. IP6K2 acts by enhancing cell-matrix adhesion and decreasing cell-cell adhesion. This action is mediated by IP7-elicited nuclear sequestration and inactivation of the tumor suppressor liver kinase B1 (LKB1). Accordingly, inhibitors of IP6K2 offer promise in cancer therapy.I nositol pyrophosphates, conserved eukaryotic messenger molecules with a pyrophosphate bond, mediate numerous physiologic processes including regulation of Akt (1), insulin secretion (2), ATP production (3), DNA repair (4), and damage response (5). Exemplified by diphosphoinositol pentakisphosphate (PPIP5, IP7), inositol pyrophosphates are primarily generated by a family of three inositol hexakisphosphate (IP6) kinases (IP6K) (6, 7) and also may be formed by a more recently described group of IP6/7 kinases (8). IP6K1 and IP6K2 are widely distributed, whereas IP6K3 is expressed primarily in the brain (9). A related enzyme, inositol polyphosphate multikinase (IPMK), converts IP3 to IP4 and IP5, displays physiologic PI3 kinase activity (10), and noncatalytically acts as a transcriptional coactivator (11) and stabilizer of the mTOR complex-1 (12). Whether IP6Ks and IPMK play direct roles in tumor progression remains unexplored.Tumor cell metastasis requires loss of cell-cell adhesion and gain of migratory and invasive properties, a collective program known as epithelial-mesenchymal transition (EMT), which is also critical for embryonic development (13). Cell-cell adhesion and cell migration/invasion are primarily driven by E-cadherinmediated cell clustering (14) and focal-adhesion-based cellmatrix interactions (15), respectively. Whether these two distinct adhesion processes are concurrently or independently regulated remains poorly understood.The tumor suppressor LKB1 has been separately reported to inhibit FAK activation (16) and to enhance E-cadherin expression (17)(18)(19). LKB1 is mutated in Peutz-Jeghers syndrome patients who tend to develop cancer at multiple sites (20). As a master kinase controlling the activity of AMPK and 13 other AMPK-like kinases (21), LKB1 mediates diverse cellular processes such as polarity, adhesion, metabolism, tumor growth/metastasis, and neuronal axon initiation/branching (22). Unlike conventional protein kinases, LKB1 is not activated by activation loop phosphorylation but by protein-protein interaction with two other subunits of the heterotrimeric holoenzyme: STRAD and Mo25. LKB1 can also exist as an inactive nuclear monomer. STRAD binds and stabilizes LKB1 (23) in the cytosol, where it is phosphorylated at serine 428 by PKCζ (24). Whether cytosolic localization enhance...

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Section: Significancesupporting

confidence: 70%

“…The tumor suppressor LKB1 has been separately reported to inhibit FAK activation (16) and to enhance E-cadherin expression (17)(18)(19). LKB1 is mutated in Peutz-Jeghers syndrome patients who tend to develop cancer at multiple sites (20).…”

mentioning

confidence: 99%

Inositol pyrophosphates promote tumor growth and metastasis by antagonizing liver kinase B1

Rao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Studies with a mouse model of non-small cell lung cancer showed that LKB1 inactivation enhanced K-RAS-mediated metastasis and affected tumor initiation and differentiation, revealing a role for LKB1 in cancer metastasis (Ji et al, 2007;Carretero et al, 2010). However, the role of LKB1 in esophageal cancer pathogenesis remains unclear.…”

Section: Lkb1 Loss Promotes Esophageal Cancer Cell Migration and Invamentioning

confidence: 99%

Altered LKB1/CREB-regulated transcription co-activator (CRTC) signaling axis promotes esophageal cancer cell migration and invasion

et al. 2011

Oncogene

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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. In this study, we observed altered LKB1-CRTC signaling in a subset of human esophageal cancer cell lines and patient samples. LKB1 negatively regulates esophageal cancer cell migration and invasion in vitro. Mechanistically, we determined that CRTC signaling becomes activated because of LKB1 loss, which results in the transcriptional activation of specific downstream targets including LYPD3, a critical mediator for LKB1 loss-of-function. Our data indicate that de-regulated LKB1-CRTC signaling might represent a crucial mechanism for esophageal cancer progression.

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“…16 Moreover, recent studies have provided strong evidences that the loss of LKB1 promotes lung carcinogenesis process, such as cell apoptosis, cycle regulation, tumor angiogenesis and metastasis. 14,17,18 The LKB1 protein as a prominent master regulator of numerous kinds of downstream kinases contributes to its tumor suppressor function. 19 It has been found that re-introduction of LKB1 in lung cancer cells can downregulate the expression of PEA3, which can suppress cell invasion by downregulation of matrix metalloproteinases (MMPs).…”

Section: Introductionmentioning

confidence: 99%

Enhanced antitumor effect of cisplatin in human NSCLC cells by tumor suppressor LKB1

Yang

et al. 2012

Cancer Gene Ther

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LKB1 is a novel candidate tumor suppressor gene in lung cancer. In this study, we evaluated the effect of cationic liposomes (LPs)-mediated LKB1 gene (LPs-pVAX-LKB1) on low-dose cisplatin (cis-diamminedichloroplatinum)-mediated antitumor activity in lung cancer, both in vitro and in vivo. Our study demonstrated that cationic LPs-mediated LKB1 gene therapy could sensitize the response of lung cancer cells to cisplatin, and significantly induce apoptosis and inhibit proliferation, invasion and metastasis, compared with control groups. Combined treatment with intratumoral administration of Lps-pVAX-LKB1 and intraperitoneal injection of low-dose cisplatin into subcutaneous A549 lung tumor xenograft resulted in significant (Po0.01) inhibition of tumor growth. Furthermore, combined treatment with intravenous injections of Lps-pVAX-LKB1 and intraperitoneal injection of low-dose cisplatin into mice bearing experimental A549 lung metastasis demonstrated significant (Po0.01) decrease in the number of lung metastatic tumor nodules. Mice life spans of combination treatment group were also dramatically prolonged, compared with controls. Further studies indicated that LKB1-enhancing cisplatin-mediated antitumor effects might be associated with the upregulation of p-p53 and p-JNK, and downregulation of p-mammalian target of rapamycin, matrix metalloproteinase (MMP)-2 and MMP-9. This study suggests that the combination of LKB1 gene therapy with low-dose cisplatin-based chemotherapy may be a potent therapeutic strategy for lung cancer.

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Integrative Genomic and Proteomic Analyses Identify Targets for Lkb1-Deficient Metastatic Lung Tumors

Cited by 216 publications

References 43 publications

Inositol pyrophosphates promote tumor growth and metastasis by antagonizing liver kinase B1

Inositol pyrophosphates promote tumor growth and metastasis by antagonizing liver kinase B1

Altered LKB1/CREB-regulated transcription co-activator (CRTC) signaling axis promotes esophageal cancer cell migration and invasion

Enhanced antitumor effect of cisplatin in human NSCLC cells by tumor suppressor LKB1

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