This document discusses the role of β-catenin in cancer therapy. It describes β-catenin as a dual function protein involved in cell adhesion and gene transcription. Mutations and overexpression of β-catenin are associated with many cancers. β-catenin is regulated by the destruction complex containing APC, and mutations in these genes lead to β-catenin accumulation and cancer development. The document reviews potential cancer therapeutic approaches targeting β-catenin, including inhibitors of its binding sites and upstream regulators in the WNT pathway.

1. ROLE OF β-CATENIN IN CANCER THERAPY
PRESENTED BY: DR. RAHUL
SHARMA
MVSc. 1st
yr
DEPARTMENT OF VETERINARY
PHARMACOLOGY AND TOXICOLOGY

2. INTRODUCTION
β-catenin is a dual function protein,involved in
regulation and coordination of cell-to-cell adhesion
and gene transcription.
In Humans ,the CTNNB1 protein is incoded bye the
CTNNB1 gene.
In Drosophila,the homologus protein is called
Armadillo
β-catenin is a subunit of cadherin poteine complex
and act as an intracellular signal transducer in the
Wnt signaling pathway.

3. β-catenin is widely expressed in many
tissues
In cardiac muscle
β-catenin localized to adherence junctions in
intercalated disc structure, which are critical for
eletrical and mechanical coupling between adjacent
cardiomyocytes.
Involved in various biological process
Embryonic brain development
Negative regulation of cell proliferation
Renal vesicle formation

4. BIOLOGICAL PROCESS LIKE
Chemical synaptic transmission
CNS vasculogenesis
Renal inner medula development
Transcription
Positive regulation of neuron apoptic process
Endoderm formation
Central role in directing several developmental
process.

5. Mutation and overexpression of β-catenin are
associated with many cancers, including
Hepatocellular carcinoma
Colorectal carcinoma
Lung cancer
Malignant breast cancer
Ovarian cancer
Endometrial cancer

6. β-catenin is regulated and destroyed by the β-catenin
destruction complex and is perticularly by
Adenomatous polyposis coli (APC) Protein, encoded
by the tumor supressing APC gene
 Therefore, genetic mutation of the APC gene is also
strongly linked to cancer, and in particular colorectal
cancer resulting from familial adenomatous polyposis
(FAP)

7. STUCTURE OF β-CATENIN
Core of β-catenin consist of several very
characterstic repeats.
Degradadtion of beta catenin is
mediated
by N-terminal segment
 the ARM domain of β-catenin
act as platform to which spicific linear motifs may bind.

8. Major role in cell-cell Adhesion
 Cell to cell adhession
beta catenin is a part of
protein complex that
forms the so called
adherens junction.
 This adhesion is
necessery for the
creation and
mentainence of epithelial
cell

9. INVOLVEMENT IN CANCER
β-CATENIN is a proto-oncogene(normal gene that
could become oncogene).mutation of this gene are
commonly found in a variety of cancers:
 Primary hepatocellular carcinoma
Colorectal cancer
Ovarial carcinoma
Breast cancer
Lung cancer
Glioblastoma

10. FINDINGS
It has been estimated that approximately 10% of all the
tissues samples sequenced from all the cancers displays
mutation in the CTNNB1 gene..
Most of these mutations clusters on a tiny area of the N-
terminal segmant of β-catenin: the β-TrCP binding motif.
Loss of function mutation of the motif essentially makes
ubiquitinylation and degradation of β-catenin imposible.

11. FIGURE
.

12. FINDINGS
Increased nuclear β- catenin level have also been noted in basal
cell carcinoma,head and neck carcinoman cell carcinoma,prostate
cancer,pilomatrixoma and meduloblastoma.
These observations may or may not implicate mutation in the β-catenin
gene: other Wnt pathway component can also be faulty.
Similar mutation are also frequently seen in the β-catenin recruiting
motifs of APC gene. Hereditary loss of function mutation of APC cause a
condition known as Familial Adenomatous Polyposis,,,in which affected
individual develops hundreds of polyps in there large intestine..most of
these are benign in nature but they have the potential to transform into
deadly cancer..

13. IMAGES
Familial Adenomatous Polyposis

14. FINDINGS
Somatic mutation of APC in colorectal cancer are also
not uncommon.
β-catenin and APC gene are among the key genes
involved in colorectal cancer development.
The potential of β-catenin to change the epithelial
phenotype of the affected cell into the invasive form
and metastasis formation…is fearful stage…

15. β-CATENIN AS A TERAPEUTIC TARGET
Due to involvement in cancer development, inhibition of beta catenin
continues to receive significant attention. But the targeting of the
binding site on its armadillo domain is not the simple task,due to its
extensive and relatively flat surface.
However for an efficient inhibition binding to a smaller ‘’HOT SPOT” is
sufficient.
This way ‘’Stapled’’ helical peptide is derived from natural beta catenin
binding motif found inLEF1 was suffient for the complete inhibition of β-
catenin dependent transcription.
Recently many small molecules compounds have been developed to
target the same. Eg: CGPO49090, PKF115-584

16. Β-CATENIN level can also be influenced by targeting
upstreme components of the Wnt Pathway as well as
the β-catenin destruction complex.
 site of the ARM domain can be Pharmacologically
targated by the Carnosic Acid.
Auxillary site is also another attractive target for
drug development.
Besides so much preclinical work there is no β-
catenin inhibitors are available as therapeutic agent
yet.

17. Another therapeutic aproach for reducing β-
catenin nuclear accumulation is via the inhibition of
galectin-3.
 The galectin-3 inhibitor GR-MD-02 is currently
undregoing clinical trials in combination with the FDA-
approved dose of Ipilimumab in patients who have
advanced melanoma.
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18. REFERENCES
Human PubMed
Mouse PubMed
Kraus C (1994)
Catalogue of sometic mutation in cancer
Clinical trials.gov

19. THANKYOU