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Page 12 of 16 Thirugnanam et al. Vessel Plus 2020;4:26 I http://dx.doi.org/10.20517/2574-1209.2020.18

and is mutated in several types of cancers [91-96] . LKB1 may inhibit cancer cell growth through regulation of
HIF-1 under hypoxic condition. Hypoxia is an important characteristic in most cancers, and induces the
expression of HIF-1 transcription factor. HIF-1 can subsequently activate genes that permit cancer cells
[97]
to survive and grow in the hypoxic tumor environment . HIF1α binds to the SNRK promotor during
ischemia, and induces it expression. SNRK protein is found in both cytoplasm and in the nucleus and
regulates genes involved in DNA synthesis and cell cycle regulation [Figure 4]. Overexpression of Snrk
decreases cell proliferation, whereas downregulation of Snrk increased cell proliferation in colon cancer
cell lines. Mechanistically, SNRK inhibits the proliferation of colon cancer cells through upregulation of
[12]
calcyclin-binding protein (CacyBP) and β-catenin degradation . CacyBP is a tumor suppressor which
has been implicated in reducing cancer cell proliferation through regulating cell cycle G1 check point in
[98]
[99]
breast , gastric , and kidney cancers [100] .
[23]
Another tumor type that depends extensively on host metabolism are ovarian cancer cells . Adipocytes in
the omentum (fat layer underlying the belly) microenvironment [101] provide fatty acids as source of energy
[24]
to ovarian cancer cells to support their rapid growth, progression, and metastasis . In ovarian cancer, the
expression of SNRK is lower in metastatic tumors and is differentially expressed depending on the stage of
[98]
the disease. This suggests that SNRK has specific roles in the disease progression of ovarian cancer and
may have diagnostic value for stratifying ovarian tumors of varying types. However, much work is needed
to realize SNRK’s full potential and its importance in cancer biology.

In summary, therapeutic strategies directed towards the enhancement of SNRK function could significantly
improve the clinical conditions associated with inflammation and metabolic dysfunction.

CONCLUDING REMARKS AND FUTURE PERSPECTIVES
A considerable amount of evidence supports the notion that SNRK activation may act as a suppressor of
inflammation and metabolic processes. Inflammation suppression comes with direct inhibition of NF-κB-
mediated inflammatory signaling, one of the signature pathways that SNRK controls. SNRK’s role in
regulating glucose and fatty acid metabolism is considered significant for the function of cardiac and
adipose tissues. Given that mitochondria is a major source of ATP production in the cell, it is not surprising
that SNRK is involved in regulating mitochondrial bioenergetic potential in CMs. Emerging evidence
in SNRK biology also suggests that it plays a defining role in cell-cell communications in various tissues
that will extend beyond adipose, renal, and cardiac tissues. In adipose tissues, SNRK plays a predominant
anti-inflammatory role. In renal tissues, endothelial SNRK protect the kidney epithelium from becoming
fibrotic. In the cardiac tissues, CMs SNRK is necessary for protecting ECs from undergoing fibrosis. In
addition, SNRK role in phosphorylating proteins (substrates) whether directly or indirectly to either
promote or inhibit its target activity/signaling pathway will need extensive evaluation and is the future of
SNRK signaling. Finally, SNRK’s role in causative human disease phenotypes will cement the importance
of this molecule from a translational biology perspective. The next 10 years of SNRK biology will be
interesting and exciting to witness, and our group along with many others will benefit from this knowledge
which we hope one day will impact patients’ lives in the form of SNRK-centric novel treatments.

DECLARATIONS
Acknowledgments
We thank Sean Palecek, PhD, University of Wisconsin-Madison for providing images that are part of the
cover picture in this series.

Authors’ contributions
Wrote drafts of the manuscript, conceptualized ideas, and provided inputs for all aspects of the manuscript
preparation: Thirugnanam K