Is POPDC1 a Potential Therapeutic Target in Various Cancers?

This report investigates the POPDC1 protein, a novel class of cAMP binding molecules, and its potential as a therapeutic target in various cancers. The introduction outlines the structure and function of POPDC proteins, emphasizing their role in maintaining cellular integrity. The literature review explores the relationship between POPDC proteins and cancer progression, highlighting how the deletion or suppression of POPDC genes can lead to increased proliferation, migration, and drug resistance. The report discusses the association between different POPDC proteins and specific cancers, such as breast cancer, hepatocellular carcinoma, and colorectal cancer. The conclusion suggests that POPDC1 could be a realistic drug target to prevent the loss of function and reduce the intensity of pathological consequences. The report recommends further research on the down-regulation of POPDC1 protein to provide conclusive evidence. References include key studies on POPDC proteins and their implications in cancer research.

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Research Title: Is POPDC1 a potential target in multiple cancers?
Introduction:
POPDC protein are broadly referred to as Popeye domain containing proteins which
are a novel class of cAMP binding molecules. A number of research studies have shown that
these proteins can affect the cell behaviour of the cancerous cells and alter the related clinical
outcome. These proteins are encoded by the family of POPDC genes which includes the
POPDC1, POPDC2 and POPDC3 genes respectively (Schindler and Brand 2013). POPDC
proteins structurally comprise of three-pass transmembrane proteins which constitute of a
short amino-terminus that are characterized with two N-glycosylation sites (Schindler and
Brand 2013). The molecular weight of POPDC1 protein is equivalent to 42kDa. It should be
noted in this context that POPDC proteins form homo-dimers which are subsequently
stabilized by disulphide bonds and helps in the maintenance of epithelial and junction
integrity. A number of research studies suggest that conserved lysines at the corboxy-terminal
end of the popeye domain in POPDC1 protein regulate the function of homo-dimerization
(Brand et al. 2014). The C terminus of the POPDC protein is located within the cytoplasm
and comprises of the popeye domain which contains a high conserved region of 150 amino
acids (Brand et al. 2014).
It should be noted in this context that the popeye domain comprises of a functional
cyclic nucleotide binding domain which facilitates the specific binding to the adenosine 3’,5’-
cyclic monophosphate (CAMP). As per Schindler and Brand (2013), it has been stated that
POPDC proteins do not bind to cGMP as the affinity factor differs by the factor 40. It should
be noted here that POPDC proteins are the five classes of eukaryotic cAMP effector proteins
which are involved in the process of protein exchange activated by cAMP.

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Fig: (a) 2-D structure of the POPDC isoforms contained in the Popeye domain
(b) 3-D structure of POPDC3
(Source: Brand 2018)
Literature Review:
Research studies predict that a structural similarity exists between Popeye domain and
other cAMP binding domains. However, it should be noted that at the sequence level only a
slight level of similarity has been detected. The major area of difference has been identified
in the phosphate binding cassette which makes direct contact with the cyclic nucleotide
(Froese et al. 2012). The structure is not similar to the phosphate binding cassette found in
other cAMP effector proteins. A study conducted by Froese et al. (2012) determined that the
cAMP affinity of the POPDC protein is 10 fold higher compared to proteins that share similar
structural properties. A number of research studies have shown that the deletion of the
POPDC genes or the suppression of the expression of the POPDC proteins led to the
progression of cancer cell properties that covered factors such as proliferation, migration,

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invasion, metastasis and drug resistance (Amunjela and Tucker 2017). However, research
findings have also established that overexpression of the POPDC proteins inhibited the
properties of invasion and metastasis.
Different POPDC Proteins connected with different kinds of Cancers:
According to Amunjela and Tucker (2017), it was stated that the suppression of the
POPDC1 protein led to the progression of tumour and yield poor clinical outcome. The
dysregulation of POPDC1 triggers the progression of breast cancer has been backed by a
number of research studies (Amunjela and Tucker 2017; Brand et al. 2014). In addition to
this, research studies have also revealed the association between reduced POPDC1 expression
and hepatocellular carcinoma as well as colorectal cancer via the activation of the c-Myc
pathway and Wnt signalling (Schindler and Brand 2016).
Conclusion:
Therefore, on the basis of the background information the association between
downstream regulation of the POPDC1 protein and progression of cancerous properties is
inevitable. This subsequently suggests that POPDC1 can be a realistic drug target for
ensuring stability of the protein and prevent the loss of function property in order to reduce
the intensity of the pathological consequences. This research intends to test the efficacy of the
POPDC1 protein as a drug target in the progression of cancers such as colorectal cancer.
Recommendation:
From the above discussion it can be deduced that the down-regulation of POPDC1
protein promotes tumorigenesis of tissues. However, there is not enough publications
available on the research topic to provide a concrete evidence and therefore, more research
focused on the down-regulation of POPDC1 protein is required for conclusive proof.

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References:
Amunjela, J.N. and Tucker, S.J., 2016. POPDC proteins as potential novel therapeutic targets
in cancer. Drug discovery today, 21(12), pp.1920-1927.
Brand, T., 2018. The popeye domain containing genes and their function as cAMP effector
proteins in striated muscle. Journal of cardiovascular development and disease, 5(1), p.18.
Brand, T., Simrick, S.L., Poon, K.L. and Schindler, R.F., 2014. The cAMP-binding Popdc
proteins have a redundant function in the heart.
Froese, A. and Brand, T., 2008. Expression pattern of Popdc2 during mouse embryogenesis
and in the adult. Developmental dynamics: an official publication of the American
Association of Anatomists, 237(3), pp.780-787.
Schindler, R.F. and Brand, T., 2016. The Popeye domain containing protein family–A novel
class of cAMP effectors with important functions in multiple tissues. Progress in biophysics
and molecular biology, 120(1-3), pp.28-36.