Hippo Pathway: Regulating Organ Size & Cell Proliferation

Background and Mechanism:

Interestingly, a few years ago it has been published in Nature magazine a study reporting that glucose, the main energy source used for energy generation in cells, regulates the Hippo pathway (specifically its downstream effector YAP)(Ref.). This is very interesting and ground breaking because with this research it has been indicated for the first time an exciting link between the glucose metabolism (glycolisis or fermentation) and the Hippo pathway and its relevance in tissue maintenance and cancer prevention.

This is also valuable since it links stronger two different views on cancer, i.e. cancer as a genetic disease and cancer as a metabolic disease.

So far we often discussed glucose metabolism (glycolisis or fermentation) but what is the Hippo Pathway?

The Hippo Pathway represents an intrinsic evolutionarily regulator of organ size essential to control and stop cell growth when the organ reaches its final size. It is involved in cell contact inhibition and controls organ size by regulating cell proliferation, apoptosis, and stem cell self renewal. Inactivation or dysregulation of this pathway leads to organ overgrowth and contributes to cancer development. (Ref1, Ref2)

The central components of this pathwacomprise
  • a regulatory serine‑threonine  kinase module and The kinase module includes the  mammalian orthologues of Drosophila mel– anogaster Hippo, mammalian STE20‑like  protein kinase 1 (MST1; also known as  STK4) and MST2 (also known as STK3),  and in addition, the large tumour suppressor 1 (LATS1) and LATS2)
  • a transcriptional  module The transcriptional module includes yes‑ associated protein (YAP) and transcrip‑ tional co‑activator with PDZ‑binding motif (TAZ; also known as WWTR1), which artwo closely related paralogues that largelmediate the downstream effects of Hippo signalling)

When the inhibitory Hippo kinase module is ‘on, LATS1 and LATS2  inactivate YAP and TAZ, and the output gene production is therefore turned off. On the other hand, when the kinase module is ‘off, YAP and TAZ translocate into the nucleus and induce target gene expressionAccordingly, the components of the kinase module are tumour suppressors and those of the transcriptional module are oncogenes.

HippoThe Hippo pathway was initially thought to be quite straightforward; however, recent studies have revealed that YAP/TAZ is an integral part and a nexus of a network composed of multiple signaling pathways, and as a result there is a crosstalk between the Hippo pathway and other tumor-related pathways (see left figure). (Ref.)

Defects in Hippo signalling and hyperactivation of its downstream Yes-associated protein (YAP) and transcriptional co-activator with TAZ contribute to the development of cancer, which suggests that pharmacological inhibition of YAP and TAZ activity may be an effective anticancer strategy.

Therefore, Yes-associated protein 1 (YAP1) is a protein that acts as a regulator by activating genes involved in cell proliferation and suppressing apoptotic genes. It is normally inhibited in the Hippo signaling pathway which allows the cellular control of organ size and tumor suppression, and is amplified in various human cancers. As a result, the YAP1 protein serves as a target for the development of new cancer drugs.

Here is a figure showing the Hippo signaling pathway http://www.cellsignal.com/contents/science-pathway-research-stem-cell-markers/hippo-signaling-pathway/pathways-hippo

Summary on the Mechanism:

In summary, the Hippo pathway regulates organ size by inhibiting cell proliferation and promoting cell apoptosis upon its activation. It is is capable of sensing and responding to the physical organization of cells, coordinating these physical signals with chemical. This sensing is done via YAP and TAZ which in turn are regulated by soluble extracellular factors, cell–cell adhesionns and mechanotransduction.

In this context, when it is active the Yes Associated Protein 1 (YAP1) affects the Hippo pathway such that promotes cell growth. In human cancer, the YAP1 gene was reported as amplified and over-expressed in several tumor types.

Note that recently it has also been identified that glucose-transporter 3 (GLUT3) is a YAP-regulated gene involved in glucose metabolism, indicating a potiantially oncogenic function of YAP in promoting glycolysis (i.e. the intensive demand of cancer cells for glucose) (Ref.)

YAP, COX2 and Celecoxib: https://www.sciencedaily.com/releases/2016/05/160525132610.htm

Direct Targeting Yes Associated Protein 1 (YAP1)

The available data do suggest the possibility that YAP/TAZ activation may be a common end-point of pathways leading to malignant progression (Ref.) Therefore, targeting YAP may prove to be a fruitful approach for treatment of multiple human cancers with aberrant YAP activity. (Ref.)

According to the study indicated above (Ref.) inhibition of YAP may also lead to the reduction of the fermentation process in cancer cells.

Indeed, it has been suggested that YAP could be a promising therapeutic strategy for treatment of e.g.
  • HCC and CCA with high YAP expression. (Ref.)
  • Higher Expression of the Oncogene YAP1, a Wnt/β-Catenin Target, is associated with Poor Outcome in Pediatric Patients with Adrenocortical Tumors (Ref.)
  • Yes-associated protein promotes tumour development in luminal epithelial derived breast cancer (Ref.)
  • Proteostasis trumps YAP in colon cancer (Ref.)
  • YAPing Hippo Forecasts a New Target for Lung Cancer (Ref.)
  • Role of Hippo-YAP signaling in Mitosis and Prostate Cancer (Ref.)
  • The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression. (Ref.)
  • etc …

Research suggests that drugs such as verteporfin, which interfere with cancer-promoting YAP function, might prove useful in Sox2-dependent tumors. (Ref.)

YAP inhibitor: Verteporfin

Verteporfin has been recently identified as YAP inhibitor:

Verteporfin (trade name Visudyne), a benzoporphyrin derivative, is a medication used as a photosensitizer for photodynamic therapy to eliminate the abnormal blood vessels in the eye. However, only recetntly it has been identified as a YAP inhibitor.

YAP is also an authophagy activator inducing resistance to Chemo: As a photosensitizer, verteporfin generates large amounts of singlet oxygen upon light irradiation, which elicits a cell-death response. In the absence of light activation, verteporfin is nontoxic and inhibits (starvation- and drug-induced) autophagy. (Ref.)

Among the 1200 compounds (green dots) Verteporfin and Auranofin (orange dots) were identified among the best hits able to induce cell death in acidic and hypoxic conditions http://www.seahorsebio.com/resources/posters/PELLEGRINI_Paola.pdf

Verteporfin Administration

10 minute in travenous infusion of Visudyne at a dose of 6 mg/m2 body surface area, diluted in in 5% glucose for injection to a final volume of 30 mL. This is the infusion solution (Ref.)

Toxicity

Most common side effects are blurred vision, headache, and local effects at the injection site. Also,photosensitivity; it is advised to avoid exposure to sunlight and unscreened lighting until 48 hours after the injection of verteporfin

Source:

Visudyne : Each vial contains 15 mg of verteporfin. After reconstitution, 1 ml contains 2 mg of verteporfin. 7.5 ml of reconstituted solution contains 15 mg of verteporfin.

Available in pharmacies, unfortunately is expensive i.e. about 1500 euro https://www.medizinfuchs.de/preisvergleich/visudyne-pulver-f.infusionsloesung-15-mg-novartis-pharma-gmbh-pzn-869382.html

We could also chose to formulate at home by solving first in DMSO and than adding Kolliphor. In this case we can buy powder at about 350euro/15mg from sources such as this one: http://www.caymaneurope.com/app/template/Product.vm/catalog/17334/tab/related/a/z;jsessionid=61738E5C5AE034B1043CEE3C4480DEBD This chemical can be identified by the following CAS number 129497-78-5

References:

Down-Regulation of Yes Associated Protein 1 Expression Reduces Cell Proliferation and Clonogenicity of Pancreatic Cancer Cells

The emerging roles of YAP and TAZ in cancer

The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment

YAP and TAZ Take Center Stage in Cancer

Molecular Pathways: YAP and TAZ Take the Centerstage in Organ Growth and Tumorigenesis

The Hippo–YAP pathway in organ size control and tumorigenesis: an updated version

YAP as oncotarget in uveal melanoma

Disclaimer:

This site is not designed to and does not provide medical advice, professional diagnosis, opinion, treatment or services to you or to any other individual. Through this site and linkages to other sites, I provide general information for educational purposes only. The information provided in this site, or through linkages to other sites, is not a substitute for medical or professional care, and you should not use the information in place of a visit, call consultation or the advice of your physician or other healthcare provider. I am not liable or responsible for any advice, course of treatment, diagnosis or any other information, services or product you obtain through this site. This is just my own personal opinion regarding what we have learned on this road.

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