Therapeutically actionable signaling node to rescue AURKA driven loss of primary cilia in VHL-deficient cells

Chowdhury, Pratim; Perera, Dimuthu; Powell, Reid T.; Talley, Tia; Tripathi, Durga Nand; Park, Yong Sung; Mancini, Michael A.; Davies, Peter J.; Stephan, Clifford; Corfa, Cristian; Dere, Ruhee

doi:10.1038/s41598-021-89933-7

Cited by 6 publications

(7 citation statements)

References 49 publications

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“…String interaction results indicated interplay of signaling molecules of AURKA pathway in SiHa/RR. AURKA was found to be strongly interacted with p53, Gadd45a, Akt and PCNA and NFκB [23][24][25]. Hyper-proliferative potential of SiHa/RR aided in increased migration and invasion capabilities as found from the result of wound healing assay where SiHa/RR lled the gap at a much faster rate compared to SiHa.…”

Section: Discussionmentioning

confidence: 86%

AURKA/NFκB Axis: A Key Determinant of Radioresistance in Cervical Squamous Carcinoma Cells

Das¹,

Ray²,

Mahapatra³

et al. 2022

Arch Clin Biomed Res

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Background: Cervical cancer being one of the leading gynaecological cancers, possess a major threat by its ever-increasing trend of global recurrence events. Radioresistance is one of the major challenges confronted during the treatment of cervical cancer. Radioresistance in cancer cells is manifested by increased rate of cellular proliferation, migration-invasion and cell cycle alterations. Aurora Kinase A (AURKA), a mitotic serine/threonine kinase was found to be overexpressed in cancers and is associated with development of acquired therapy resistance. The principal objective of this study revolved with exploring the mechanisms by which AURKA confers radioadaptive response in cervical cancer cells.Methods and Results: Parental cervical squamous carcinoma cell line SiHa was subjected to recurrent insult by fractionated dose of X-irradiation. Finally, a resistant subline (SiHa/RR) was isolated at 40Gy. SiHa/RR exhibited higher expression of AURKA/ pAURKA along with the signaling molecules that are favored by this kinase (HIF1α, pAkt, NFκB) vis-à-vis lower expressions of the molecules that are generally suppressed by AURKA (p53, Gadd45a). Surprisingly, inhibition of AURKA in SiHa/RR showed improved radiosensitivity by reducing the wound healing capacity, sphere forming ability and enhancing radiation induced apoptosis. Ectopic overexpression of AURKA gave rise to radioresistant phenotype in parental SiHa by stimulating nuclear translocation of NFκB. This pattern of increased nuclear localization of NFκB was also observed in resistant subline as a consequence of activation and overexpression of AURKA.Conclusion: These ndings strengthened the involvement of AURKA in radioresistance via activating NFκB mediated signaling pathway to deliver radioresistant associated adaptive complexities.

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Section: Discussionmentioning

confidence: 86%

AURKA/NFκB Axis: A Key Determinant of Radioresistance in Cervical Squamous Carcinoma Cells

Das¹,

Ray²,

Mahapatra³

et al. 2022

Arch Clin Biomed Res

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“…VHL-deficient cells are not ciliated and exhibit defects in cellular polarity and cell-cycle regulation, leading to uncontrolled cell proliferation ( 233 , 234 ). Interestingly, VHL also acts as a E3-ubiquitin ligase, and in this capacity, targets the ciliary disassembly factor Aurora Kinase A (AURKA) for degradation ( 235 ). Moreover, loss of VHL function results in high levels of AURKA, affecting stability of the microtubular axoneme and leading to disassembly of the primary cilium followed by development of cystic kidneys and RCC ( 235 ).…”

Section: Primary Cilium In Renal Cell Carcinomasmentioning

confidence: 99%

Primary cilia and actin regulatory pathways in renal ciliopathies

Kalot,

Sentell,

Kitzler

et al. 2024

Front. Nephrol.

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Ciliopathies are a group of rare genetic disorders caused by defects to the structure or function of the primary cilium. They often affect multiple organs, leading to brain malformations, congenital heart defects, and anomalies of the retina or skeletal system. Kidney abnormalities are among the most frequent ciliopathic phenotypes manifesting as smaller, dysplastic, and cystic kidneys that are often accompanied by renal fibrosis. Many renal ciliopathies cause chronic kidney disease and often progress to end-stage renal disease, necessitating replacing therapies. There are more than 35 known ciliopathies; each is a rare hereditary condition, yet collectively they account for a significant proportion of chronic kidney disease worldwide. The primary cilium is a tiny microtubule-based organelle at the apex of almost all vertebrate cells. It serves as a “cellular antenna” surveying environment outside the cell and transducing this information inside the cell to trigger multiple signaling responses crucial for tissue morphogenesis and homeostasis. Hundreds of proteins and unique cellular mechanisms are involved in cilia formation. Recent evidence suggests that actin remodeling and regulation at the base of the primary cilium strongly impacts ciliogenesis. In this review, we provide an overview of the structure and function of the primary cilium, focusing on the role of actin cytoskeleton and its regulators in ciliogenesis. We then describe the key clinical, genetic, and molecular aspects of renal ciliopathies. We highlight what is known about actin regulation in the pathogenesis of these diseases with the aim to consider these recent molecular findings as potential therapeutic targets for renal ciliopathies.

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“…In mouse embryonic fibroblasts, VHL binds to AKT1 hydroxylated at Pro125 and Pro314 by Phd2, which results in suppression of AKT kinase activity but does not increase its degradation [ 186 , 187 ]. In human RPE cells, loss of primary cilia caused by VHL depletion can be rescued by AKT inhibition [ 188 ].…”

Section: Akt Signaling and Its Regulation In Primary Ciliamentioning

confidence: 99%

“…This disease is associated with a severe reduction in the frequency of primary cilia [ 59 ] and hyperactivation of the PI3K–AKT signaling cascade [ 192 ]. Interestingly, inhibition of AKT in VHL-deficient cells decreases the expression of AURKA [ 188 ]. Therefore, inhibition of VHL–AKT signaling may be one approach to suppress the proliferation of RCC through stimulation of ciliogenesis.…”

Section: Akt Signaling and Its Regulation In Primary Ciliamentioning

confidence: 99%

Aurora A and AKT Kinase Signaling Associated with Primary Cilia

Nishimura

Yamakawa

Shiromizu

et al. 2021

Cells

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Dysregulation of kinase signaling is associated with various pathological conditions, including cancer, inflammation, and autoimmunity; consequently, the kinases involved have become major therapeutic targets. While kinase signaling pathways play crucial roles in multiple cellular processes, the precise manner in which their dysregulation contributes to disease is dependent on the context; for example, the cell/tissue type or subcellular localization of the kinase or substrate. Thus, context-selective targeting of dysregulated kinases may serve to increase the therapeutic specificity while reducing off-target adverse effects. Primary cilia are antenna-like structures that extend from the plasma membrane and function by detecting extracellular cues and transducing signals into the cell. Cilia formation and signaling are dynamically regulated through context-dependent mechanisms; as such, dysregulation of primary cilia contributes to disease in a variety of ways. Here, we review the involvement of primary cilia-associated signaling through aurora A and AKT kinases with respect to cancer, obesity, and other ciliopathies.

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Therapeutically actionable signaling node to rescue AURKA driven loss of primary cilia in VHL-deficient cells

Cited by 6 publications

References 49 publications

AURKA/NFκB Axis: A Key Determinant of Radioresistance in Cervical Squamous Carcinoma Cells

AURKA/NFκB Axis: A Key Determinant of Radioresistance in Cervical Squamous Carcinoma Cells

Primary cilia and actin regulatory pathways in renal ciliopathies

Aurora A and AKT Kinase Signaling Associated with Primary Cilia

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