Verteporfin without light stimulation inhibits YAP activation in trabecular meshwork cells: Implications for glaucoma treatment

Chen, Weisheng; Cao, Zhiyi; Krishnan, Chandrasekharan; Panjwani, Noorjahan

doi:10.1016/j.bbrc.2015.09.012

Cited by 42 publications

(40 citation statements)

References 27 publications

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“…5, S15, S16). Previous work with 2D substrates showed that YAP/TAZ silencing led to decreased cell spreading, focal adhesion size, and collagen I gene expression [30] and also demonstrated that VP inhibition reduced cell contractility and expression of the YAP target gene Ctgf [31]. Indeed, we observed reduced MSC spreading and nuclear YAP/TAZ in both 2D and 3D cultures treated with either VP or CytoD.…”

Section: Discussionsupporting

confidence: 74%

Dimensionality and spreading influence MSC YAP/TAZ signaling in hydrogel environments

et al. 2016

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Improved fundamental understanding of how cells interpret microenvironmental signals is integral to designing better biomaterial therapies. YAP/TAZ are key mediators of mechanosensitive signaling; however, it is not clear how they are regulated by the complex interplay of microenvironmental factors (e.g., stiffness and degradability) and culture dimensionality. Using covalently crosslinked norbornene-functionalized hyaluronic acid (HA) hydrogels with controlled stiffness (via crosslink density) and degradability (via susceptibility of crosslinks to proteolysis), we found that human mesenchymal stem cells (MSCs) displayed increased spreading and YAP/TAZ nuclear localization when cultured atop stiffer hydrogels; however, the opposite trend was observed when MSCs were encapsulated within degradable hydrogels. When stiffnessmatched hydrogels of reduced degradability were used, YAP/TAZ nuclear translocation was greater in cells that were able to spread, which was confirmed through pharmacological inhibition of YAP/TAZ and actin polymerization. Together, these data illustrate that YAP/TAZ signaling is responsive to hydrogel stiffness and degradability, but the outcome is dependent on the dimensionality of cell-biomaterial interactions.

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Section: Discussionsupporting

confidence: 74%

Dimensionality and spreading influence MSC YAP/TAZ signaling in hydrogel environments

et al. 2016

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“…Deoxysappanone is a component of green tea and has been shown to possess anti-diabetic properties by activating mitochondria 45 . Verteporfin is a benzoporphyrin used as a photosensitizer in photodynamic therapy to treat macular degeneration 46 . The mechanism of inhibition of HIF target gene expression by these compounds cannot be explained by effect on HIF protein expression.…”

Section: Discussionmentioning

confidence: 99%

Multidimensional Screening Platform for Simultaneously Targeting Oncogenic KRAS and Hypoxia-Inducible Factors Pathways in Colorectal Cancer

Bousquet

Jia

Ratnayake³

et al. 2016

ACS Chem. Biol.

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Colorectal cancer (CRC) is a genetic disease, due to progressive accumulation of mutations in oncogenes and tumor suppressor genes. Large scale genomic sequencing projects revealed >100 mutations in any individual CRC. Many of these mutations are likely passenger mutations and fewer are driver mutations. Of these, activating mutations in RAS proteins are essential for cancer initiation, progression, and/or resistance to therapy. There has been significant interest in developing drugs targeting mutated cancer gene products or downstream signaling pathways. Due to the number of mutations involved and inherent redundancy in intracellular signaling, drugs targeting one mutation or pathway have been either ineffective or led to rapid resistance. We have devised a strategy whereby multiple cancer pathways may be simultaneously targeted for drug discovery. For proof-of-concept, we targeted the oncogenic KRAS, and HIF pathways, since oncogenic KRAS has been shown to be required for cancer initiation and progression, and HIF-1α and HIF-2α are induced by the majority of mutated oncogenes and tumor suppressor genes in CRC. We have generated isogenic cell lines defective in either oncogenic KRAS or both HIF-1α and HIF-2α, and subjected them to multiplex genomic, siRNA, and high-throughput small molecule screening. We have identified potential drug targets and compounds for preclinical and clinical development. Screening of our marine natural product library led to the rediscovery of the microtubule agent dolastatin 10 and the class I histone deacetylase (HDAC) inhibitor largazole to inhibit oncogenic KRAS and HIF pathways. Largazole was further validated as an anti-angiogenic agent in a HIF-dependent manner in human cells and in vivo in zebrafish using a genetic model with activated HIF. Our general strategy, coupling functional genomics with drug susceptibility or chemical-genetic interaction screens, enables the identification of potential drug targets and candidates with requisite selectivity. Molecules prioritized in this manner can easily be validated in suitable zebrafish models due to the genetic tractability of the system. Our multidimensional platform with cellular and organismal components can be extended to larger scale multiplex screens that include other mutations and pathways.

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“…Therefore, in the present study, we tested several doses of verteporfin, which have also been used in previously published articles. 34,35 Before treatment, cells were starved overnight in serum-free Dulbecco's Modified Eagle's Medium (DMEM; Wako Pure Chemical Industries, Osaka, Japan).…”

Section: Cell Stimulationmentioning

confidence: 99%

YAP/TAZ Are Essential for TGF-β2–Mediated Conjunctival Fibrosis

Futakuchi

Inoue

Wei

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To investigate the roles of Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ), the major effector molecules of the Hippo pathway, in TGFb2-mediated conjunctival fibrosis.METHODS. Primary human conjunctival fibroblasts were treated with TGF-b2. The expression of YAP/TAZ was examined by Western blot analyses and immunocytochemistry. The expression of fibrotic proteins and genes were evaluated by Western blot analyses and quantitative real-time PCR, respectively. The effects of YAP/TAZ on fibrotic changes were examined by knockdown experiments and the YAP/TAZ inhibitor, verteporfin.RESULTS. TGF-b2 stabilized YAP/TAZ and subsequently activated Smad2/3, which led to the transcription of fibrotic genes in human primary conjunctival fibroblasts. These fibrotic genes were differently regulated by YAP/TAZ. Notably, a-smooth muscle actin, fibronectin, collagen I, and collagen IV were primarily regulated by YAP. In contrast, CCN family proteins (CTGF and CYR61) depended on both YAP and TAZ. Mechanistically, YAP/TAZ were located in close proximity to Smad2/3, and in particular, YAP was required for TGF-b2-mediated phosphorylation and the nuclear translocation of Smad2/3. Furthermore, a YAP/TAZ inhibitor markedly suppressed TGF-b2-mediated fibrotic changes in conjunctival fibroblasts.CONCLUSIONS. YAP/TAZ acted as a molecular hub of TGF-b2 signaling in a cellular model of conjunctival fibrosis. Moreover, verteporfin, a YAP/TAZ inhibitor exerted potent antifibrosis effects by suppressing TGF-b2-YAP/TAZ-Smad signaling. Our study highlights YAP/TAZ as essential regulators of conjunctival fibrosis and shows that inhibition of YAP/TAZ might potentially improve the outcomes of glaucoma filtration surgery.

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Verteporfin without light stimulation inhibits YAP activation in trabecular meshwork cells: Implications for glaucoma treatment

Cited by 42 publications

References 27 publications

Dimensionality and spreading influence MSC YAP/TAZ signaling in hydrogel environments

Dimensionality and spreading influence MSC YAP/TAZ signaling in hydrogel environments

Multidimensional Screening Platform for Simultaneously Targeting Oncogenic KRAS and Hypoxia-Inducible Factors Pathways in Colorectal Cancer

YAP/TAZ Are Essential for TGF-β2–Mediated Conjunctival Fibrosis

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