WNT1-inducible signaling pathway protein-1 activates diverse cell survival pathways and blocks doxorubicin-induced cardiomyocyte death

Venkatesan, Balachandar; Prabhu, Sumanth D.; Venkatachalam, Karthikeyan; Mummidi, Srinivas; Valente, Anthony J.; Clark, Robert A.; Delafontaine, Patrick; Chandrasekar, Bysani

doi:10.1016/j.cellsig.2010.01.005

Cited by 100 publications

(145 citation statements)

References 56 publications

(93 reference statements)

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“…For example, WISP1, an effector of activated Wnt signaling previously reported to regulate cell survival, [17][18][19] showed the highest level change (3.6-fold higher in U373-IR than in U373-C). Patient data at the US National Cancer Institute (Repository of Molecular Brain Neoplasia Data (REMBRANDT) 20,21 ) also indicated that upregulation of WISP1 is associated with poorer clinical outcome (Supplementary Figure S2), further substantiating our data.…”

Section: Microarray Analysis Reveals Upregulated Wnt Signaling In U37mentioning

confidence: 99%

Wnt activation is implicated in glioblastoma radioresistance

Kim

Lee

et al. 2012

Laboratory Investigation

140

105

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Glioblastoma (GBM) patients have dismal median survival even with the most rigorous treatments currently available. Radiotherapy is the most effective non-surgical therapy for GBM patients; however, patients succumb due to tumor recurrence within a year. To develop a curative therapeutic approach, we need to better understand the underlying molecular mechanism of radiation resistance in GBM. Towards this goal, we developed an in vivo orthotopic GBM model system that mimics the radiation response of human GBM, using both established-GBM cell line and patient-derived freshly dissociated GBM specimen. In-vivo ionizing radiation (IR) treatment prolonged the survival of mice with intracranical tumor derived from U373MG, but failed to prevent tumor recurrence. U373MG and GBM578 cells isolated after in-vivo IR (U373-IR and 578-IR) were more clonogenic and enriched with stem cell-like characteristics, compared with mock-treated control tumor cells. Transcriptomic analyses and quantitative real-time reverse-transcription PCR analyses using these matched GBM cells before and after radiation treatment revealed that Wnt pathways were preferentially activated in post-IR GBM cells. U373-IR cells and 578-IR were enriched with cells positive for both active b-catenin (ABC) and Sox2 population, and this subpopulation was further increased after additional in-vitro radiation treatment, suggesting that radiation resistance of GBM is mediated due, in part, to the activation of stem cell-associated pathways including Wnt. Finally, pharmacological and siRNA inhibition of Wnt pathway significantly decreased the survival and clonogenicity of GBM cells and reduced their ABC þ /Sox2 þ population. Together, these data suggest that Wnt activation is a molecular mechanism to confer GBM radioresistance and an important therapeutic target.

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Section: Microarray Analysis Reveals Upregulated Wnt Signaling In U37mentioning

confidence: 99%

Wnt activation is implicated in glioblastoma radioresistance

Kim

Lee

et al. 2012

Laboratory Investigation

140

105

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“…Although multiple cellular pathways may account for the cytoprotective capacity of WISP1 [7,8,10,11,20,21], recent work suggests that mTOR may play a significant role in providing cellular protection with WISP1 [13]. Yet, cellular protection by mTOR may require a level of modulation since high mTOR activity has been associated with apoptotic cell death [43].…”

Section: Discussionmentioning

confidence: 99%

“…WISP1 has been demonstrated to rely upon the phosphorylation and activation of phosphatidylinositol-3-kinase (PI 3-K) and protein kinase B (Akt) [7,8,10,11,20,21] as well as the mammalian target of rapamycin (mTOR) [13] to promote cellular protection. In addition, mTOR phosphorylates and activates p70S6K at threonine 389 and is a marker of mTOR activity [40].…”

Section: Wisp1 Modulates the Post-translational Phosphorylation Of Akmentioning

confidence: 99%

“…The CCN protein family consists of six secreted extracellular matrix associated proteins with four cysteine-rich modular domains that include insulin-like growth factorbinding domain, von Willebrand factor type C module, thrombospondin domain, and Cterminal cysteine knot-like domain [4]. WISP1 has a cytoprotective role during bone repair [5], renal injury [6,7], cardiac cell injury [8], and lung epithelial cell damage [9]. Interestingly, WISP1 has been shown to be protective against oxidative stress in neurons [10][11][12] and to block amyloid toxicity in inflammatory microglia of the brain [13].…”

Section: Introductionmentioning

confidence: 99%

“…WISP1 promotes cytoprotection in multiple cell types through pathways that not only require phosphatidylinositol-3-kinase (PI 3-K) and protein kinase B (Akt) [7,8,10,11,20,21], but also utilize pathways in microglia that involve the mammalian target of rapamycin (mTOR) and the proline rich Akt substrate 40 kDa (PRAS40) [13]. mTOR is the catalytic component of two mTOR complexes termed mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) [22,23].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Tuberous Sclerosis Protein 2 (TSC2) Modulates CCN4 Cytoprotection During Apoptotic Amyloid Toxicity in Microglia

Shang¹,

Chong²,

Wang³

et al. 2012

CNR

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More than 110 million individuals will suffer from cognitive loss worldwide by the year 2050 with a majority of individuals presenting with Alzheimer's disease (AD). Yet, successful treatments for etiologies that involve β-amyloid (Aβ) toxicity in AD remain elusive and await novel avenues for drug development. Here we show that Wnt1 inducible signaling pathway protein 1 (WISP1/ CCN4) controls the post-translational phosphorylation of Akt1, p70S6K, and AMP activated protein kinase (AMPK) to the extent that tuberous sclerosis complex 2 (TSC2) (Ser 1387 ) phosphorylation, a target of AMPK, is decreased and TSC2 (Thr 1462 ) phosphorylation, a target of Akt1, is increased. The ability of WISP1 to limit TSC2 activity allows WISP1 to increase the activity of p70S6K, since gene silencing of TSC2 further enhances WISP1 phosphorylation of p70S6K. However, a minimal level of TSC2 activity is necessary to modulate WISP1 cytoprotection that may require modulation of mTOR activity, since gene knockdown of TSC2 impairs the ability of WISP1 to protect microglia against apoptotic membrane phosphatidylserine (PS) exposure, nuclear DNA degradation, mitochondrial membrane depolarization, and cytochrome c release during Aβ exposure.

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Expression of FAP, ADAM12, WISP1, and SOX11 is heterogeneous in aggressive fibromatosis and spatially relates to the histologic features of tumor activity

et al. 2013

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Aggressive fibromatosis (AF) represents a group of tumors with a variable and unpredictable clinical course, characterized by a monoclonal proliferation of myofibroblastic cells. The optimal treatment for AF remains unclear. Identification and validation of genes whose expression patterns are associated with AF may elucidate biological mechanisms in AF, and aid treatment selection. This study was designed to examine the protein expression by immunohistochemistry (IHC) of four genes, ADAM12, FAP, SOX11, and WISP1, that were found in an earlier study to be uniquely overexpressed in AF compared with normal tissues. Digital image analysis was performed to evaluate inter- and intratumor heterogeneity, and correlate protein expression with histologic features, including a histopathologic assessment of tumor activity, defined by nuclear chromatin density ratio (CDR). AF tumors exhibited marked inter- and intratumor histologic heterogeneity. Pathologic assessment of tumor activity and digital assessment of average nuclear size and CDR were all significantly correlated. IHC revealed protein expression of all four genes. IHC staining for ADAM12, FAP, and WISP1 correlated with CDR and was higher, whereas SOX11 staining was lower in tumors with earlier recurrence following excision. All four proteins were expressed, and the regional variation in tumor activity within and among AF cases was demonstrated. A spatial correlation between protein expression and nuclear morphology was observed. IHC also correlated with the probability of recurrence following excision. These proteins may be involved in AF pathogenesis and the corresponding pathways could serve as potential targets of therapy.

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WNT1-inducible signaling pathway protein-1 activates diverse cell survival pathways and blocks doxorubicin-induced cardiomyocyte death

Cited by 100 publications

References 56 publications

Wnt activation is implicated in glioblastoma radioresistance

Wnt activation is implicated in glioblastoma radioresistance

Tuberous Sclerosis Protein 2 (TSC2) Modulates CCN4 Cytoprotection During Apoptotic Amyloid Toxicity in Microglia

Expression of FAP, ADAM12, WISP1, and SOX11 is heterogeneous in aggressive fibromatosis and spatially relates to the histologic features of tumor activity

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