Targeting the Hippo Pathway for Anti-cancer Therapies

The Hippo signaling pathway is involved in tissue size regulation and tumorigenesis. Genetic deletion or aberrant expression of some Hippo pathway genes lead to enhanced cell proliferation, tumorigenesis, and cancer metastasis. Recently, multiple studies have identified a wide range of upstream regulators of the Hippo pathway, including mechanical cues and ligands of G protein-coupled receptors (GPCRs). Through the activation related G proteins and possibly rearrangements of actin cytoskeleton, GPCR signaling can potently modulate the phosphorylation states and activity of YAP and TAZ, two homologous oncogenic transcriptional co-activators, and major effectors of the Hippo pathway. Herein, we summarize the network, regulation, and functions of GPCR-Hippo signaling, and we will also discuss potential anti-cancer therapies targeting GPCR-YAP signaling.

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Localized JNK signaling regulates organ size during development

eLife ◽

10.7554/elife.11491 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 20

Author(s):

Helen Rankin Willsey ◽

Xiaoyan Zheng ◽

José Carlos Pastor-Pareja ◽

A Jeremy Willsey ◽

Philip A Beachy ◽

...

Keyword(s):

Hedgehog Signaling ◽

Hippo Pathway ◽

Size Control ◽

Organ Size ◽

Control Mechanisms ◽

Cancer Therapies ◽

Independent Manner ◽

Jnk Signaling ◽

New Strategy ◽

The Hippo Pathway

A fundamental question of biology is what determines organ size. Despite demonstrations that factors within organs determine their sizes, intrinsic size control mechanisms remain elusive. Here we show that Drosophila wing size is regulated by JNK signaling during development. JNK is active in a stripe along the center of developing wings, and modulating JNK signaling within this stripe changes organ size. This JNK stripe influences proliferation in a non-canonical, Jun-independent manner by inhibiting the Hippo pathway. Localized JNK activity is established by Hedgehog signaling, where Ci elevates dTRAF1 expression. As the dTRAF1 homolog, TRAF4, is amplified in numerous cancers, these findings provide a new mechanism for how the Hedgehog pathway could contribute to tumorigenesis, and, more importantly, provides a new strategy for cancer therapies. Finally, modulation of JNK signaling centers in developing antennae and legs changes their sizes, suggesting a more generalizable role for JNK signaling in developmental organ size control.

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Hippo pathway mediates resistance to cytotoxic drugs

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1703096114 ◽

2017 ◽

Vol 114 (18) ◽

pp. E3729-E3738 ◽

Cited By ~ 22

Author(s):

Taranjit S. Gujral ◽

Marc W. Kirschner

Keyword(s):

Cell Lines ◽

Hippo Pathway ◽

Active Form ◽

Hippo Signaling ◽

Cancer Therapies ◽

Multidrug Transporters ◽

Hippo Signaling Pathway ◽

Patient Derived Xenograft ◽

Xenograft Models ◽

The Hippo Pathway

Chemotherapy is widely used for cancer treatment, but its effectiveness is limited by drug resistance. Here, we report a mechanism by which cell density activates the Hippo pathway, which in turn inactivates YAP, leading to changes in the regulation of genes that control the intracellular concentrations of gemcitabine and several other US Food and Drug Administration (FDA)-approved oncology drugs. Hippo inactivation sensitizes a diverse panel of cell lines and human tumors to gemcitabine in 3D spheroid, mouse xenografts, and patient-derived xenograft models. Nuclear YAP enhances gemcitabine effectiveness by down-regulating multidrug transporters as well by converting gemcitabine to a less active form, both leading to its increased intracellular availability. Cancer cell lines carrying genetic aberrations that impair the Hippo signaling pathway showed heightened sensitivity to gemcitabine. These findings suggest that “switching off” of the Hippo–YAP pathway could help to prevent or reverse resistance to some cancer therapies.

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A Study of Abemaciclib (LY2835219) in Combination With Other Anti-Cancer Therapies in Japanese Participants With Advanced Cancer

Case Medical Research ◽

10.31525/ct1-nct04071262 ◽

2019 ◽

Author(s):

Keyword(s):

Advanced Cancer ◽

Cancer Therapies ◽

Anti Cancer

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ANTICANCER EFFECT OF UVARIA GENUS

Journal of Medicine and Pharmacy ◽

10.34071/jmp.2013.6.16 ◽

2014 ◽

pp. 98-101

Author(s):

Thi Bich Hien Le ◽

Viet Duc Ho ◽

Thi Hoai Nguyen

Keyword(s):

Biological Activities ◽

Current Trend ◽

Healthcare Systems ◽

Chemical Compositions ◽

Cancer Therapies ◽

Pharmacological Effects ◽

Anticancer Effect ◽

Anti Cancer ◽

Tropical Areas ◽

Cancer Activity

Nowadays, cancer treatment has been a big challenge to healthcare systems. Most of clinical anti-cancer therapies are toxic and cause adverse effects to human body. Therefore, current trend in science is seeking and screening of natural compounds which possess antineoplastic activities to utilize in treatment. Uvaria L. - Annonaceae includes approximately 175 species spreading over tropical areas of Asia, Australia, Africa and America. Studies on chemical compositions and pharmacological effects of Uvaria showed that several compound classes in this genus such as alkaloid, flavonoid, cyclohexen derivaties, acetogenin, steroid, terpenoid, etc. indicate considerable biological activities, for example anti-tumor, anti-cancer, antibacterial, antifungal, antioxidant, etc. Specifically, anti-cancer activity of fractions of extract and pure isolated compounds stands out for cytotoxicity against many cancer cell lines. This study provides an overview of anti-cancer activity of Uvaria and suggests a potential for further studies on seeking and developing novel anti-cancer compounds. Key words: Anti-cancer, Uvaria.

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