Tracing PAKs from GI inflammation to cancer

Dammann, Kyle; Khare, Vineeta; Gasché, Christoph

doi:10.1136/gutjnl-2014-306768

Cited by 59 publications

(66 citation statements)

References 160 publications

(236 reference statements)

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“…Aberrant PAK1 plays a critical role in tumor cell proliferation and invasiveness, thereby modulating oncogenesis and tumorigenic progression (21,22). Because PAK1 has been recognized as a potential pharmacological molecular target, the clinical pipeline of molecular therapy targeting PAK1 has been growing (21)(22)(23). Our previous studies and those of other investigators demonstrated that PAK1 is up-regulated in cancers of the gastrointestinal tract, including GC (23)(24)(25)(26)(27)(28).…”

Section: Significancementioning

confidence: 96%

“…Among the multiple oncoproteins, a serine/threonine protein kinase designated "p21-activated kinase 1" (PAK1), which is stimulated by active Rac1 and Cdc42-GTPases, works as a node of cancersignaling networks (21,22). PAK1 overexpression has been observed frequently in a variety of cancers.…”

Section: Significancementioning

confidence: 99%

“…PAK1 overexpression has been observed frequently in a variety of cancers. Aberrant PAK1 plays a critical role in tumor cell proliferation and invasiveness, thereby modulating oncogenesis and tumorigenic progression (21,22). Because PAK1 has been recognized as a potential pharmacological molecular target, the clinical pipeline of molecular therapy targeting PAK1 has been growing (21)(22)(23).…”

Section: Significancementioning

confidence: 99%

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Growth hormone-releasing hormone receptor antagonists inhibit human gastric cancer through downregulation of PAK1–STAT3/NF-κB signaling

Gan

Jiang

et al. 2016

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

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Gastric cancer (GC) ranks as the fourth most frequent in incidence and second in mortality among all cancers worldwide. The development of effective treatment approaches is an urgent requirement. Growth hormone-releasing hormone (GHRH) and GHRH receptor (GHRH-R) have been found to be present in a variety of tumoral tissues and cell lines. Therefore the inhibition of GHRH-R was proposed as a promising approach for the treatment of these cancers. However, little is known about GHRH-R and the relevant therapy in human GC. By survival analyses of multiple cohorts of GC patients, we identified that increased GHRH-R in tumor specimens correlates with poor survival and is an independent predictor of patient prognosis. We next showed that MIA-602, a highly potent GHRH-R antagonist, effectively inhibited GC growth in cultured cells. Further, this inhibitory effect was verified in multiple models of human GC cell lines xenografted into nude mice. Mechanistically, GHRH-R antagonists target GHRH-R and down-regulate the p21-activated kinase 1 (PAK1)-mediated signal transducer and activator of transcription 3 (STAT3)/nuclear factor-κB (NF-κB) inflammatory pathway. Overall, our studies establish GHRH-R as a potential molecular target in human GC and suggest treatment with GHRH-R antagonist as a promising therapeutic intervention for this cancer.GHRH receptor | GHRH-R antagonist | PAK1 | stomach cancer | prognostic predictor

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Section: Significancementioning

confidence: 96%

Section: Significancementioning

confidence: 99%

Section: Significancementioning

confidence: 99%

See 1 more Smart Citation

Growth hormone-releasing hormone receptor antagonists inhibit human gastric cancer through downregulation of PAK1–STAT3/NF-κB signaling

Gan

Jiang

et al. 2016

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

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“…More of these studies in the future are likely to shape a better understanding of PAKs. Our appreciation for the role of PAKs in vast number of human diseases such as cancer (Kumar and Li, 2016), inflammation (Dammann, Khare, Gasche, 2014), neurological disorders (Ma et al, 2012), cardiovascular disorders (Ke et al, 2014), and viral diseases (Van den Broeke et al, 2010) is likely to grow. The breadth and scope of developing and improving next generation PAK modifiers will likely gain momentum and may extend to many diseases.…”

Section: Future Of Paksmentioning

confidence: 99%

Structure, biochemistry, and biology of PAK kinases

Kumar

Sanawar

et al. 2017

Gene

181

192

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PAKs, p21-activated kinases, play central roles and act as converging junctions for discrete signals elicited on the cell surface and for a number of intracellular signaling cascades. PAKs phosphorylate a vast number of substrates and act by remodeling cytoskeleton, employing scaffolding, and relocating to distinct subcellular compartments. PAKs affect wide range of processes that are crucial to the cell from regulation of cell motility, survival, redox, metabolism, cell cycle, proliferation, transformation, stress, inflammation, to gene expression. Understandably, their dysregulation disrupts cellular homeostasis and severely impacts key cell functions, and many of those are implicated in a number of human diseases including cancers, neurological disorders, and cardiac disorders. Here we provide an overview of the members of the PAK family and their current status. We give special emphasis to PAK1 and PAK4, the prototypes of groups I and II, for their profound roles in cancer, the nervous system, and the heart. We also highlight other family members. We provide our perspective on the current advancements, their growing importance as strategic therapeutic targets, and our vision on the future of PAKs.

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“…Accumulating evidence suggests that PAK1 signaling actively participates in gut homeostasis (12). Within intestinal crypts, PAK1 facilitates cell proliferation through sustainment of Wnt/ b-catenin signaling (13,14).…”

Section: Introductionmentioning

confidence: 99%

PAK1 Promotes Intestinal Tumor Initiation

Dammann

Khare

Harpain

et al. 2015

Cancer Prevention Research

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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.

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Tracing PAKs from GI inflammation to cancer

Cited by 59 publications

References 160 publications

Growth hormone-releasing hormone receptor antagonists inhibit human gastric cancer through downregulation of PAK1–STAT3/NF-κB signaling

Growth hormone-releasing hormone receptor antagonists inhibit human gastric cancer through downregulation of PAK1–STAT3/NF-κB signaling

Structure, biochemistry, and biology of PAK kinases

PAK1 Promotes Intestinal Tumor Initiation

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