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

Jagadeeshan, Sankar; Subramanian, Anirudh; Tentu, Shilpa; Beesetti, Swarnalatha; Singhal, Mahak; Raghavan, Swetha; Surabhi, Rohan Prasad; Mavuluri, Jayadev; Bhoopalan, Hemdev; Biswal, Jayashree; Pitani, Ravi Shankar; Chidambaram, Swathikan; Sundaram, Sandhya; Malathi, R.; Jeyakanthan, Jeyaraman; Nair, Asha S.; Venkatraman, Ganesh; Rayala, Suresh K.

doi:10.1093/annonc/mdw184

Cited by 42 publications

(26 citation statements)

References 22 publications

(26 reference statements)

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“…This protein is presented as a regulator of cytoskeletal remodeling, apoptosis and cell motility. It has been recently demonstrated that nephrotoxicity increases matrix remodeling and apoptosis properties [34,35]. We also report Cdk9, Psma3, Icam1, Myc, Hnrpu, Pak1 and Alb as a consensus early signature of nephrotoxicity that induced by Lead acetate.…”

Section: Discussionsupporting

confidence: 56%

Molecular Mechanisms Underlying the Nephrotoxicity of Cisplatin, Lead Acetate and Cyclosporine: Key Roles of Myc and Smad4

Askari¹,

Abdullahi²,

Poortahmasebi³

et al. 2017

Biol syst Open Access

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It is well documented that use of Cisplatin, Lead acetate and Cyclosporine in the chemotherapy and medical interventions is highly associated with nephrotoxicity and interrelated comorbidities. Here, we proposed the possible molecular mechanisms responsible for nephrotoxicity of these compounds. We utilized the microarray dataset GSE59913 consisting of approximately 600 different compounds profiled in up to 8 different tissues. After analysis with GEO2R, gene expression profiles of three aforementioned compounds were integrated with protein-protein interactions (PPI) networks and topological properties of the networks were measured using Cytoscape software. We found several key genes and signaling pathways that seem to be involved in nephrotoxicity of the examined compounds. Myc and Smad4 were identified as principal players of three compounds' nephrotoxicity through various pathways. Our results revealed the critical functions of Il2, Jak-Stat, Mapk-Pi3k, TGFβ and Ca 2+ signaling pathways as well as novel biomarkers that may mediate the nephrotoxicity of Cisplatin, Lead acetate and Cyclosporine. The significantly altered genes in the compound-treated samples were substantially correlated with regulation of cell proliferation, apoptosis, inflammatory responses and homeostatic processes. This study reveals the important hub genes, biological networks and key pathways as well as novel biomarkers involved in nephrotoxicity of Cisplatin, Lead acetate and Cyclosporine.

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Section: Discussionsupporting

confidence: 56%

Molecular Mechanisms Underlying the Nephrotoxicity of Cisplatin, Lead Acetate and Cyclosporine: Key Roles of Myc and Smad4

Askari¹,

Abdullahi²,

Poortahmasebi³

et al. 2017

Biol syst Open Access

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“…Recently, several reports [4,9,11,15] unraveled the role of Pak1 in the activation of pancreatic stellate cells (PSCs), its involvement in transforming normal pancreatic cells to PDAC and its ability to modulate drug resistance in pancreatic cancer. All these findings suggest that Pak1-specific inhibitors will prove to be a better adjuvant with the existing chemotherapy modality for PDAC.…”

Section: Expert Opinionmentioning

confidence: 99%

“…One possible impeding factor which is difficult to achieve is the selectivity within the PAK family, because of sequence homology among the family members. Although some Pak1 selective inhibitors like IPA-3 [9,[16][17][18][19], FRAX-597 [11,20], G-5555 [12], and Novartis compound 3 [13] have been disclosed, the successful in vivo dose optimization for target specificity and stability is yet to be tested on larger group of animals. …”

Section: Expert Opinionmentioning

confidence: 99%

“…On the other hand, Pak1 being an established survival signaling molecule may also protect pancreatic cancer cells from adverse effects of chemotherapy via multiple signaling crosstalks. Therefore, combinatorial therapeutic strategies capable of managing these detrimental effects of Pak1 need to be tailored to effectively handle pancreatic cancer [9]. Also, it was reported that targeting RAC-Pak1 signaling in RASdriven cancers using Pak1 deletion or Pak1 inhibitor could efficiently regress tumor growth in vivo [10].…”

mentioning

confidence: 99%

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

Jagadeeshan

Venkatraman

Rayala

2016

Expert Opinion on Therapeutic Targets

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“…PAK1 also contributes to therapeutic resistance of cancers of the pancreas [4], colon [5] and lung [1], and thus may become an important target in cancer treatment. We have previously reported that PAK1 stimulates growth and metastasis of colorectal cancer (CRC), through activation of multiple signalling molecules including ERK, AKT [6] and β-catenin [7].…”

Section: Introductionmentioning

confidence: 99%

Depletion of p21-activated kinase 1 up-regulates the immune system of APC∆14/+ mice and inhibits intestinal tumorigenesis

et al. 2017

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BackgroundP21-activated kinase 1 (PAK1) stimulates growth and metastasis of colorectal cancer (CRC) through activation of multiple signalling pathways. Up-regulation of CRC stem cell markers by PAK1 also contributes to the resistance of CRC to 5-fluorouracil. The aim of this study was to investigate the effect of PAK1 depletion and inhibition on the immune system and on intestinal tumour formation in APC∆14/+ mice.MethodsThe PAK1 KO APC∆14/+ mice were generated by cross-breeding of PAK1 KO mice with APC∆14/+ mice. Splenic lymphocytes were analysed by flow cytometry, and immunohistochemical staining. The numbers of intestinal tumours were counted. Blood cells were also counted.ResultsCompared to APC+/+ mice, the numbers of both T- and B- lymphocytes were reduced in the spleen of APC∆14/+ mice. Depletion of PAK1 in APC∆14/+ mice increased the numbers of splenic T- and B- lymphocytes and decreased the numbers of intestinal tumours. Treatment of APC∆14/+ mice with PF-3758309, a PAK inhibitor reduced the numbers of intestinal tumours and increased the numbers of blood lymphocytes.ConclusionDepletion of active PAK1 up-regulates the immune system of APC∆14/+ mice and suppresses intestinal tumour development. These observations suggest an important role for PAK1 in the immune response to tumours.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3432-0) contains supplementary material, which is available to authorized users.

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

Abstract: To our knowledge, 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.

Cited by 42 publications

References 22 publications

Molecular Mechanisms Underlying the Nephrotoxicity of Cisplatin, Lead Acetate and Cyclosporine: Key Roles of Myc and Smad4

Molecular Mechanisms Underlying the Nephrotoxicity of Cisplatin, Lead Acetate and Cyclosporine: Key Roles of Myc and Smad4

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

Depletion of p21-activated kinase 1 up-regulates the immune system of APC∆14/+ mice and inhibits intestinal tumorigenesis

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