P-21 activated kinase 1 knockdown inhibits β-catenin signalling and blocks colorectal cancer growth

He, Hong; Huynh, Nhi; Liu, Kevin H.; Malcontenti‐Wilson, Caterina; Zhu, Jun; Christophi, Christopher; Shulkes, Arthur; Baldwin, Graham S.

doi:10.1016/j.canlet.2011.11.014

Cited by 48 publications

(53 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5-ASA treatment, and not PAK1 deletion, reduced inflammation in this AOM/DSS model, implicating a PAK1-independent effect of 5-ASA on intestinal inflammation. He and colleagues reported that PAK1 knockdown reduced tumor growth using a xenograft model (20). We, however, did not observe this phenotype upon PAK1 deletion in either of our APC min or AOM/DSS models.…”

Section: Discussioncontrasting

confidence: 79%

See 1 more Smart Citation

PAK1 Promotes Intestinal Tumor Initiation

Dammann

Khare

Harpain

et al. 2015

Cancer Prevention Research

View full text Add to dashboard Cite

p21-activated kinase 1 (PAK1) is a serine/threonine kinase that is overexpressed in colorectal cancer. PAK1 is a target of mesalamine [5-aminosylicylic acid (5-ASA)], a common drug for the treatment of ulcerative colitis with prospective chemopreventive properties. Here, we investigated whether PAK1 deletion impedes tumorigenesis in murine intestinal cancer models. Ten-week-old APC min or APC min /PAK1 À/À mice were monitored for 8 weeks, euthanized, and assessed for tumor number and size. Six-to 8-week-old PAK1 À/À and wild-type (WT) mice received one 10 mg/kg intraperitoneal injection of azoxymethane (AOM) and four cycles of 1.7% dextran sodium sulfate (DSS) for 4 days followed by 14 days of regular water. Mice also received 5-ASA via diet. Tumor incidence and size was assessed via colonoscopy and pathology. Molecular targets of PAK1 and 5-ASA were evaluated via immunohistochemistry (IHC) in both models. PAK1 deletion reduced tumor multiplicity and tumor burden but did not alter average tumor size in APC min mice. IHC revealed that PAK1 deletion reduced p-AKT, b-catenin, and c-Myc expression in APC min adenomas. Colonoscopy and pathologic analysis revealed that PAK1 deletion reduced tumor multiplicity without affecting tumor size in AOM/DSS-treated mice. 5-ASA treatment and PAK1 deletion impeded tumor multiplicity and dysplastic lesions in AOM/DSS mice. IHC further revealed that 5-ASA blocked b-catenin signaling via inhibition of PAK1/p-AKT. These data indicate that PAK1 contributes to initiation of intestinal carcinogenesis.

show abstract

Section: Discussioncontrasting

confidence: 79%

“…Previous reports established that PAK1 expression increases with colorectal cancer progression (19) and have shown that knockdown of PAK1 within xenograft models reduces tumor size (20). However, it is unclear whether PAK1 deletion interferes with intestinal tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

PAK1 Promotes Intestinal Tumor Initiation

Dammann

Khare

Harpain

et al. 2015

Cancer Prevention Research

View full text Add to dashboard Cite

show abstract

“…For instance, in gastric cells, PAK1 modification of b-catenin was previously shown to lead to b-catenin nuclear localization and subsequent activation of MYC transcription. 33 However, we did not find this effect in AML cells (data not shown). In FLT3-ITDexpressing myeloproliferative disease, PAK1 inhibition reduced the presence of activated nuclear signal transducer and activator of transcription 5 (STAT5), leading to reduced transcription of MYC.…”

Section: Discussionmentioning

confidence: 61%

PAK1 is a therapeutic target in acute myeloid leukemia and myelodysplastic syndrome

Pandolfi

Stanley

et al. 2015

Blood

View full text Add to dashboard Cite

show abstract

“…Knockdown of PAK4 reduced the proliferation and survival of ovarian cancer cells (20), pancreatic cancer 8988T cells (18), JEG3, and JAR choriocarcinoma cells (33) and increased the levels of apoptotic proteins in gastric cancer cell lines (34). In comparison, knockdown of PAK1 inhibited the anchorage-dependent (14) and -independent (35) growth of breast cancer cells, the proliferation of NSCLC cancers in vitro and in vivo (14), colon cancer in vitro (27) and in vivo (28), and the growth of gastric cancer cells anchorage-dependently and -independently as well as tumor xenografts (36). In previous studies, gene amplification or increased protein expression of PAK4 or PAK1 has been suggested to correlate with dependence on this pathway for tumor progression and tumor cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…Knockdown of PAK1 in DLD1 cells with a specific shRNA inhibited cell migration, invasion, and proliferation in vitro via extracellular signal-regulated kinase (ERK)-and AKT-dependent pathways (27). Likewise, knockdown of PAK1 in HCT116 colon carcinoma cells inhibited b-catenin expression and transcriptional activity, and inhibited colon cancer growth in vivo (28).…”

Section: Introductionmentioning

confidence: 99%

Knockdown of PAK4 or PAK1 Inhibits the Proliferation of Mutant KRAS Colon Cancer Cells Independently of RAF/MEK/ERK and PI3K/AKT Signaling

Tabusa

Brooks

Massey

2013

Molecular Cancer Research

View full text Add to dashboard Cite

The p21-activated kinase (PAK) serine/threonine kinases are important effectors of the small GTPases Rac and Cdc42, and play significant roles in controlling cell growth, motility, and transformation. Knockdown of PAK4 or PAK1 inhibited the proliferation of mutant KRAS or BRAF colon cancer cells in vitro. Dependence on PAK4 or PAK1 protein for colon cancer cell proliferation was independent of PAK4 or PAK1 protein expression levels. Mutant KRAS HCT116 colorectal cells were the most sensitive to PAK4 or PAK1 knockdown resulting in the potent inhibition of anchorage-dependent and -independent proliferation as well as the formation and proliferation of HCT116 colon cancer spheroids. This inhibition of proliferation did not correlate with inhibition of RAF/MEK/ ERK or PI3K/AKT signaling. In HCT116 cells, knockdown of PAK4 or PAK1 caused changes to the actin cytoskeleton resulting in reduced basal spread and cell elongation and increased cell rounding. These cytoskeletal rearrangements seemed to be independent of LIMK/cofilin/paxillin phosphorylation. PAK4 or PAK1 knockdown initially induced growth arrest in HCT116 cells followed by cell death at later time points. Inhibition of the antiapoptotic proteins Bcl-2 and Bcl-X L with the pharmacologic inhibitor ABT-737 increased effector caspase activation and apoptosis, and reduced cell survival with PAK4 or PAK1 knockdown. These results support a role for the PAKs in the proliferation of mutant KRAS-driven colorectal carcinoma cells via pathways not involving RAF/MEK/ERK and PI3K/AKT signaling. Mol Cancer Res; 11(2); 109-21. Ó2012 AACR.

show abstract

P-21 activated kinase 1 knockdown inhibits β-catenin signalling and blocks colorectal cancer growth

Cited by 48 publications

References 25 publications

PAK1 Promotes Intestinal Tumor Initiation

PAK1 Promotes Intestinal Tumor Initiation

PAK1 is a therapeutic target in acute myeloid leukemia and myelodysplastic syndrome

Knockdown of PAK4 or PAK1 Inhibits the Proliferation of Mutant KRAS Colon Cancer Cells Independently of RAF/MEK/ERK and PI3K/AKT Signaling

Contact Info

Product

Resources

About