Transcriptional regulation of fibronectin by p21-activated kinase-1 modulates pancreatic tumorigenesis

@article{Jagadeeshan2014TranscriptionalRO,
  title={Transcriptional regulation of fibronectin by p21-activated kinase-1 modulates pancreatic tumorigenesis},
  author={Sankar Jagadeeshan and Yoganathan Ramia Krishnamoorthy and Mahak Singhal and A Subramanian and Jayadev Mavuluri and A. Vijaya Lakshmi and Arivazhagan Roshini and Ganga Baskar and M Ravi and L DeRisi Joseph and Kalesh Sadasivan and Aswini R. Krishnan and Asha S Nair and Ganesh Venkatraman and Suresh Kumar Rayala},
  journal={Oncogene},
  year={2014},
  volume={34},
  pages={455-464}
}
Pancreatic ductal adenocarcinoma (PDAC) is the eighth largest cause of cancer-related mortality across the world, with a median 5-year survival rate of less than 3.5%. This is partly because the molecules and the molecular mechanisms that contribute to PDAC are not well understood. Our goal is to understand the role of p21-activated kinase 1 (Pak1) signaling axis in the progression of PDAC. Pak1, a serine/threonine kinase, is a well-known regulator of cytoskeletal remodeling, cell motility… 

P21-activated kinase 1 (Pak1) signaling influences therapeutic outcome in pancreatic cancer.

This is the first study illustrating the mechanistic role of Pak1 in causing gemcitabine resistance via multiple signaling crosstalks, and hence Pak1-specific inhibitors will prove to be a better adjuvant with existing chemotherapy modality for PDAC.

Targeting p21 activated kinase 1 (Pak1) to PAKup Pancreatic Cancer

This is one of the first molecular studies to examine the role of Pak1 pathway in the involvement of pancreatic cancer and identified fibronectin, a component of the extracellular matrix, as a transcriptional target ofPak1 signaling.

Reduced expression of p21-activated protein kinase 1 correlates with poor histological differentiation in pancreatic cancer

It is reported for the first time that PAK1 is a novel prognostic marker for pathologically confirmed human pancreatic cancer.

Identification of a novel PAK1 inhibitor to treat pancreatic cancer

MYB Promotes Desmoplasia in Pancreatic Cancer through Direct Transcriptional Up-regulation and Cooperative Action of Sonic Hedgehog and Adrenomedullin*

MYB is identified as novel regulator of pancreatic tumor desmoplasia, which is suggestive of its diverse roles in PC pathobiology.

FRAX597, a PAK1 inhibitor, synergistically reduces pancreatic cancer growth when combined with gemcitabine

These results implicate PAK1 as a regulator of pancreatic cancer cell growth and survival and combined with cytotoxic chemotherapy deserves further study as a novel therapeutic approach to Pancreatic cancer treatment.

p21-activated kinase signalling in pancreatic cancer: New insights into tumour biology and immune modulation

The pivotal role of PAKs in Kras-driven pancreatic cancer is highlighted in terms of tumour biology and chemo-resistance, and the involvement of PAks in immune modulation in the tumour microenvironment is discussed and the potential advantages of targetingPAKs are explored.

References

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Targeting p21-activated kinase 1 (PAK1) to induce apoptosis of tumor cells

Evidence is provided for dysregulation of PAK1 in breast and squamous NSCLCs and a role for PAK2 in cellular survival and proliferation in these indications and several synergistic combination therapies, including combination with antagonists of inhibitor of apoptosis proteins, were revealed.

Genomic alterations link Rho family of GTPases to the highly invasive phenotype of pancreas cancer

It is determined that RIOK3 promotes its invasive activities through activation of the small G protein, Rac, which prompted a genome wide survey of other components of the Rho family network, revealing p21 Activated Kinase 4 (PAK4) as another amplified gene in PDAC tumors and cell lines.

Targeting phosphoinositide 3-kinase pathways in pancreatic cancer--from molecular signalling to clinical trials.

This review will discuss how the PI3K/Akt/mTOR signaling network is altered in pancreatic cancer and further give an overview of preclinical and clinical studies where this pathway has been targeted.

p21-activated Kinase-1 Signaling Mediates Cyclin D1 Expression in Mammary Epithelial and Cancer Cells*

Findings suggest a model wherein Pak1 regulation of cyclin D1 expression might involve an NF-κB-dependent pathway and that hyperplasia in the mammary glands of Pak1-TG mice may be associated, at least in part, with the up-regulation of cyclIn D1, and that Pak1 is up-regulated in human breast tumors.

PAK signaling in cancer

Although PAKs are not mutated in cancers, they are overexpressed, hyperactivated or amplified in several human tumors and their role in cell transformation make them attractive therapeutic targets.

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A key role is proposed for PAK action in coordinating the dynamics of the actin and microtubule cytoskeletons during directional motility of cells, as well as in other functions requiring cytOSkeletal polarization.

Nuclear Localization and Chromatin Targets of p21-activated Kinase 1*

Investigations provide proof-of-principle evidence that Pak1 could influence the expression of its putative chromatin targets in both a positive and a negative manner, opening new avenues to further the search for nuclear Pak1 functions and identify putative Pak1-interacting nuclear proteins.

p21-activated kinases in cancer

Paks are well-known regulators of cytoskeletal remodelling and cell motility, but have recently been shown to promote cell proliferation, regulate apoptosis and accelerate mitotic abnormalities, which results in tumour formation and cell invasiveness.

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The p21-activated kinases (PAKs) are central players in growth factor signaling networks and morphogenetic processes that control proliferation, cell polarity, invasion and actin cytoskeleton