High nuclear β-catenin levels confer resistance to AKT inhibition and coordinates with increased nuclear FOXO3a to promote metastasis in colon cancer.

Slides:

Advertisements

Similar presentations

Targeting signal transduction

Advertisements

A B SK-N-SH cells, 24 h after irradiation SK-N-SH cells, 48 h

Targeting the PARP DNA repair pathway enhanced cytotoxicity induced by chemotherapy. Targeting the PARP DNA repair pathway enhanced cytotoxicity induced.

Strategies for differential inhibition of mTORC1 and mTORC2 with rapamycin. Strategies for differential inhibition of mTORC1 and mTORC2 with rapamycin.

Underlying Mechanisms for Distant Metastasis - Molecular Biology

MAPK pathway inhibitors.

PTEN (a.k.a. MMAC1 and TEP1) and Cowden’s Disease

PI3K isoform–selective inhibitors and PTEN induction decrease ERK phosphorylation. PI3K isoform–selective inhibitors and PTEN induction decrease ERK phosphorylation.

Figure 4 Possible combination therapies CDK4/6 inhibitors

Sustained signaling through the B-cell receptor induces Mcl-1 and promotes survival of chronic lymphocytic leukemia B cells by Aleksandar Petlickovski,

Figure 1 A schematic representation of the HER2 signalling pathway

Mechanisms of apoptosis and growth arrest by isothiocyanates.

Volume 141, Issue 6, Pages (December 2011)

Methed-Up FOXOs Can't In-Akt-ivate

Caught in the Akt: Regulation of Wnt Signaling in the Intestine

Wnt/β-Catenin Signaling: Turning the Switch

AKT dependence of ovarian cancer cell lines.

Wnt Signaling: It Gets More Humorous with Age

Dongwon Kim, Luis A. Garza Journal of Investigative Dermatology

A20 inhibits caspase-8 cleavage and TRAIL-induced apoptosis.

The EGF receptor confers BRAF inhibitor resistance in BRAF-mutant melanoma cells. The EGF receptor confers BRAF inhibitor resistance in BRAF-mutant melanoma.

High-throughput combination drug screening to nominate potent drug combinations. High-throughput combination drug screening to nominate potent drug combinations.

NOTCH and PI3K-AKT Pathways Intertwined

Model of the BET and MEK inhibitor combination therapy to treat melanoma with NRAS mutation and immune therapy resistance Model of the BET and MEK inhibitor.

Activated membrane signaling promotes survival in response to radiation. Activated membrane signaling promotes survival in response to radiation. Radiation.

Signaling induced by BRAF L597R and L597S is sensitive to BRAF and MEK inhibitors. Signaling induced by BRAF L597R and L597S is sensitive to BRAF and MEK.

Nat. Rev. Urol. doi: /nrurol

A and B, CO-1686–resistant NCI-H1975 cell clones, COR1-1 and COR10-1 display a reduced dependence on EGFR signaling for survival. A and B, CO-1686–resistant.

Genes frequently mutated in colorectal cancer and their relationships with miRNAs. Genes frequently mutated in colorectal cancer and their relationships.

Transfection of stable β-catenin (S33Y) increased nuclear β-catenin and phosphorylated Akt expression (A) and reduced the promoting effect of HG on caspase-3.

Smoothing Out Drug Resistance

Fig. 3. Inactivation of the Wnt/β-catenin signaling pathway inhibited cell proliferation and induced apoptosis in A549 and SPC-A-1 cells. Inactivation.

GPC5 Gene and Its Related Pathways in Lung Cancer

Inhibition of FL accumulation by glutathione and a size range of its conjugates. Inhibition of FL accumulation by glutathione and a size range of its conjugates.

FL accumulation in Malpighian tubules of Drosophila, and its inhibition by several potential substrates. FL accumulation in Malpighian tubules of Drosophila,

Knocking down Wnt3 increases the cells' response to trastuzumab and reduces cells' invasiveness. Knocking down Wnt3 increases the cells' response to trastuzumab.

Alterations in the Rap1 and PI3K–Akt signaling in afadin cKO mice.

Exosome-mediated inhibition of T cells is reversible.

Nat. Rev. Rheumatol. doi: /nrrheum

Volume 4, Issue 4, Pages (April 2009)

BCL-3 does not mediate β-catenin activity through promoting nuclear translocation or altering levels of LEF1. BCL-3 does not mediate β-catenin activity.

Single-Dose Neoadjuvant AKT Pathway Inhibitor Reduces Growth of Hepatocellular Carcinoma after Laser Thermal Ablation in a Small Animal Model Neoadjuvant PI3K/mTOR/AKT inhibitor prior.

A, B, apoptosis analysis using Annexin V-FITC/PI was done on 5th, 7th, and 9th day after transfection either with si control or si AEBP1in U87MG and U138MG.

A, PTEN loss signature score in resected SQCLC brain metastases.

MiR-200c is a PI3K–AKT signaling pathway regulator in CRC

IL-13Rα2 promotes cell survival and proliferation.

Experimental metastasis inhibition by primary tumors is mediated by NK cells and IFNγ. Experimental metastasis inhibition by primary tumors is mediated.

Expression of versican promoted breast cancer cell self-renewal through enhanced EGFR/AKT/GSK-3β (S9P) signals. Expression of versican promoted breast.

Discovery of Gö6976-related potent reversible EGFR T790M inhibitors.

Activation of Wnt signaling pathway in trastuzumab-resistant cell lines. Activation of Wnt signaling pathway in trastuzumab-resistant cell lines. A, bar.

GPC3 promotes hepatocellular carcinoma growth by stimulating the canonical Wnt pathway (A-B) GPC3 induces the stabilization of cytoplasmic β-catenin. GPC3.

Per1 inhibits growth and induces apoptosis in prostate cancer cell lines. Per1 inhibits growth and induces apoptosis in prostate cancer cell lines. LNCaP,

Potential model of HMQ1611 inhibiting breast cancer cell proliferation

Changes in signal transduction pathway induced by gefitinib.

IGF-I partially protects Rh30 cells from apoptosis despite simultaneous inhibition of PI3K-Akt and MAP kinase pathways. IGF-I partially protects Rh30 cells.

The CD8+ cytotoxic T-cell response in Ron TK−/− hosts in response to tumors is necessary and sufficient to block metastasis. The CD8+ cytotoxic T-cell.

High-throughput drug screen (HTDS) reveals ARS1620 and PI3K pathway inhibitors synergies and a heterogeneous pattern of RTK synergies. High-throughput.

The critical roles of miR-23a and miR-27a in colorectal cancer progression. miR-23a primarily increases cell motility through downregulation of its target.

Effect of silencing β-catenin on the invasion and metastasis of MHCC97 and Hep3B cells under normoxic and hypoxic conditions. Effect of silencing β-catenin.

Schematic representation of signaling pathways associated with cannabinoid receptor activation induced by its agonists. Schematic representation of signaling.

Validation of MYC-driven drug responses.

The role of RAI2 in breast cancer metastasis.

Phosphorylation of Twist1 in human breast cancer cell lines and tumors

HER2 and PI3K-targeted therapies result in FOXO3a-mediated feedback upregulation of HER3 and IGF1R and provide an escape from PI3K pathway inhibition.

Compartmentalized cellular functions of KDM4A.

MTOR kinase inhibition–induced reactivation of AKT substrates is HER2 and PI3K dependent. mTOR kinase inhibition–induced reactivation of AKT substrates.

EPHA2 inhibitors inhibit phosphorylation of AKT and ERK, arrest cell cycle at G0–G1, and induce apoptosis in both vemurafenib (VEM)-sensitive and VEM-resistant.

Genomic and proteomic profiling of ovarian cancer cell lines.

Knockdown of ROR1 increases the invasive potential of melanoma cells in vitro and in vivo. Knockdown of ROR1 increases the invasive potential of melanoma.

AXL is not necessary for maintenance of intrinsic resistance.

Presentation transcript:

High nuclear β-catenin levels confer resistance to AKT inhibition and coordinates with increased nuclear FOXO3a to promote metastasis in colon cancer. High nuclear β-catenin levels confer resistance to AKT inhibition and coordinates with increased nuclear FOXO3a to promote metastasis in colon cancer. A, activation of the Wnt/β-catenin leads to nuclear accumulation of β-catenin, and activation of the PI3K–AKT pathway inhibits nuclear translocation of FOXO3a. B, the presence of high nuclear β-catenin and increased nuclear FOXO3a results in resistance to PI3K pathway inhibitors and promotes cell scattering and metastasis. C, reducing nuclear β-catenin through Wnt/β-catenin pathway inhibition reverses the metastatic potential and resistance to PI3K/AKT inhibitors, resulting in increased apoptosis. Dotted lines represent multiple steps not shown graphically, and line strength represents relative activation. LEF, lymphoid enhancer factor; TCF, T-cell factor. Samuel J. Klempner et al. Cancer Discovery 2013;3:1345-1354 ©2013 by American Association for Cancer Research