Figure 5. Enriched PTMs in Celecoxib-treated and untreated
samples. The PTMs of Celecoxib- targets were shown by triangle and
others by circle.
Discussion
Celecoxib is one of the top-selling NSAID medicines in the world
[60]. Also, NSAIDs involve 5%-10% of the remedy of all
prescriptions per year [37, 61]. There are some reports that show
the possible indication of celecoxib with the neurodegenerative diseases
associated with inflammatory processes [62-66]. Though celecoxib can
pass through the BBB and access to the CNS, reports about side effects
of celecoxib [67, 68] are related to cardiovascular diseases rather
than the nervous system [12]. In other words, the major molecular
footprints of this medicine on central nervous system (CNS) are not
well-described [12]. Indeed, as we expected, we observed that most
of the introduced targets of celecoxib in different databases are not
related to CNS. Considering the essential role of celecoxib in the
treatment of pain and inflammation, and its influence on the CNS, our
study aimed to characterize protein targets of this drug especially in
the nervous system.
One of the identified celecoxib-targets is Rab-2A, which is a GTPase
required for protein transport from the endoplasmic reticulum to the
Golgi complex by regulating COPI-dependent vesicular transport [69,
70]. This protein was common between TPP-identified targets and the
PDP database (Fig. 2C). PDP is a powerful up-to-date web resource that
unifies various commercial and public bioactive compound libraries
[53]. To explore the role of Rab2A in detail, Sugawara et al.studied the effect of Rab2A knockdown on glucose-stimulated insulin
secretion and the Golgi intermediate compartment in the corresponding
cells. They reported that inactivation of Rab2A mitigated
glucose-induced ER stress and inhibited apoptosis induced by ER stress
through enlarging of the endoplasmic reticulum (ER)-Golgi intermediate
compartment [71]. Therefore, it seems that celecoxib is associated
with apoptosis by targeting Rab-2A and implicating ER stress. Providing
more evidence through testing celecoxib on the same cells, insulinoma
cells, to clarify the celecoxib influence on the ER stress is warranted.
Also, TPP-identified proteins were enriched in pathways related to
neurodegenerative disease and cancer. Interestingly, the anticancer
activity of celecoxib has been reported in various models of animal
tumors, and it is proposed that this drug is beneficial for the
prevention and treatment of cancer [72-74]. The molecular mechanisms
of antitumoral effects of celecoxib have become a challenging issue,
since some reports showed that the effect of celecoxib on cancer is
apart from COX-2 inhibition, meaning that celecoxib has other targets
than COX-2 [2, 75, 76]. Several components as intermediate
candidates have been proposed for the anticancer effects of celecoxib,
the most common of which is the sarco/endoplasmic reticulum Ca2+-ATPase
(SERCA) [1, 77, 78]. Our CC enrichment analysis also disclosed that
the endoplasmic reticulum lumen annotation was statistically enriched in
TPP-identified proteins, such that several of the proteins involved in
the pathways that regulate calcium concentrations, including ERO1A,
ARSB, NOL3, STIM1, CALCR, SDF4, and BAX (Figure 4). Interestingly, it
has been previously shown that celecoxib increases the intracellular
concentration of calcium by inhibiting SERCA [1, 77-79] and the
long-term leakage of calcium from the endoplasmic reticulum acts as a
potent stimulant of ER stress, which finally leads to cell death and
exerts its effect on cancer [77, 80].
Several members of the Ras-associated binding (Rab) family are obviously
expressed in various cancer tissues, and dysregulation of Rab expression
could be tumorigenic or tumor-suppressive [81]. The Rab family plays
an essential role in multiple aspects of membrane trafficking control.
Therefore, vesicle transport regulators play crucial roles in the
mediation of cancer cell biology, including uncontrolled cell growth,
invasion, and metastasis. The Rabs, like other members of the Ras
superfamily, function as molecular switches through changes in its
guanine nucleotide-binding status between the active GTP-bound and
inactive GDP-bound forms. In its active, GTP-bound form, Rabs could
mediate vesicular transport by allowing transport carriers or vesicles
to engage specific effectors such as motor proteins and tethering
factors, as well as vesicle fusion with the engagement of soluble
N-ethylmaleimide sensitive factor (NSF) [82] attachment receptor
(SNARE) [83, 84] proteins. Vesicle delivery and dynamics are
critical for regulating cell behavior associated with cell
migration/invasion and tumorigenesis. Cooperation between Rabs and
effectors in mediating vesicle movement pathways has significant
influences on tumor progression and malignancy. Therefore, it raises the
possibility that targeting a particular trafficking system may provide a
new approach to cancer treatment [85]. As shown in this study,
celecoxib targeted proteins, i.e., RAB2A, RAB10, and RAB11B are notably
involved in Rab protein signal transduction. As shown in Figure 4B,
TPP-identified proteins are enriched in GDP binding, GTPase activity,
and protein phosphatase inhibitor activity that change the GTPases and,
as a result, involve in mechanisms associated with cancer. Therefore, it
seems that studying the effect of celecoxib on cancer models by TPP
provide more supporting evidence.
Neurodegenerative diseases are also assigned to TPP-identified targets
of celecoxib as an anti-inflammatory drug. Recent studies demonstrated
that neuronal inflammation is a vital trigger of neurological diseases
[66], and it exacerbates disorders including Alzheimer ’s -,
Parkinsons - , Huntingtons diseases, as well as amyotrophic lateral
sclerosis and multiple sclerosis [62-65]. In the present study, some
of the mentioned neurodegenerative disorders were enriched based on
phenotypic-based biological annotations, such as schizophrenia and
depression. Twelve of 44 TPP-identified celecoxib targets are involved
in Alzheimer’s disease metabolism, suggesting a high possibility of
celecoxib involvement in the mechanisms of this neurodegenerative
disease. Notably, inflammation of the nervous system is observed in
these disorders, and it is accompanied by an increase in inflammatory
cytokines [86-88]. We also illustrated that celecoxib could be
beneficial in treating the diseases mentioned above that are associated
with inflammation by affecting the biosynthesis pathway of
prostaglandins by the involvement of four identified proteins, i.e.,
DCTN1, PSIP1, BAX and AMPH.
Finally, we describe the importance of PTMs for the thermal stability of
proteins. We show that multiple PTMs are involved in the protein
thermostability. For example, acetylation, which significantly affects
the life span of intracellular proteins by avoiding intracellular
proteases degradation, is enriched in all TPP-identified proteins [89,
90]. Citrullination is the specific PTM identified in celecoxib
treated sample (See Fig. 5). It is related to the change of arginine to
citrulline, which strongly affects the structure and function of
proteins in both physiological and pathological processes such as
apoptosis, multiple sclerosis, and Alzheimer’s disease [91-93].
Interestingly, an important diagnostic tool in the painful inflammatory
disease such as Rheumatoid arthritis is to use anti-cyclic citrullinated
peptide (anti-CCP) antibodies which detect citrullination levels of the
patients and NSAIDs including Celecoxib are usually prescribed for those
patients [94, 95]. Our findings highlight the role of citrullinated
proteins as a target of Celecoxib.
Conclusion
Although phenotypic-based screens have become increasingly popular in
drug discovery, the major challenge of this approach is the mechanistic
deconvolution of the putative drug action during screening. The
promising TPP approach has been introduced and expanded to tackle such
challenges. In the present study, targets of celecoxib within rat
hippocampus were characterized using TPP as a high throughput target
discovery approach.
We show that celecoxib plays an effector role in several signaling
pathways and biological processes, which can be linked to various
diseases such as neurodegenerative disorders and cancer. Therefore, in
addition to inhibiting COX2, we illustrate that celecoxib might modify
also other pathways. Our findings support the pharmaceutical reports
related to the repurposing of celecoxib for cancer and neurodegenerative
disorders [96-98]. It seems that celecoxib is potentially beneficial
for treating cancer by inhibiting SERCA and increasing the intracellular
concentration of calcium, which causes ER stress along with cell death.
Another proposed mechanism is affecting the trafficking system since
transport regulators play essential roles in the mediation of cancer
cell biology and especially circulating tumor cells. We found a
significant effect of this medicine on proteins involved in the
trafficking system of cells.
On the other hand, neuronal inflammation is a major culprit of
neurodegenerative diseases, proteins of which were significantly
enriched in the present study. Inflammation in CNS starts by stimulation
of astrocytes, and it continues with entering environmental immune cells
to the brain. This process causes overproduction of cytokines, nitric
oxide, active oxygen species, prostaglandins and eventually damage and
cause death of neurons [36, 66, 68, 88]. Our findings support the
idea of using celecoxib for neuronal inflammation due to the explored
association of celecoxib targets and the inflammation.
To conclude, we identified several novelCelecoxib protein targets using
TPP, which could be of interest in order to modify several pathways in
CNS. Our findings provide new molecular evidence for celecoxib to be
used as an add-on therapy in neurodegenerative disorders and cancer.
However, more preclinical and paraclinical evidence is required to
suggest the true drug repurposing potential of celecoxib.
Author contribution
EG and RK performed experiments, contributed to data analysis,
interpretation and manuscript first-draft writing. AK, MS, KG and HR
contributed to sampling, performing drug treatment and protein
extraction. RS and MB contributed to do mass spectrometry analysis. ZT
contributed to bioinformatic data gathering. HR, RS, MJ and JT also
contributed to data interpretation and manuscript writing. MJ, RJ, JT
and MB conceived and commenced the project and provided direction on
study design and feedback on the final results.
Acknowledgement
The authors also acknowledge Dr. Rozbeh Jafari and Dr. Farnaz Barneh
for helpful comments. This study was financially supported by the
National Institute for Medical Research Development of Iran (NIMAD)
(Elite Grants, Grant No.964580), Academy of Finland (No. 317680) and
European Research Council (No. 716063).
Competing Interests’
Statement
None
Supplementary files
Supplementary file 1: Whole soluble protein concentrations at a
range of temperature and celecoxib concentrations. The horizontal axis
represents temperature, and the vertical axis shows protein
concentration. Each section is dedicated to a particular celecoxib
concentration, DMSO-control, and water control. As demonstrated by
increasing the temperature, we have a significant decrease in protein
concentration.
Supplementary file 2: The distribution of the expression
profile of Rab-2A, one of the TPP-identified protein targets, across the
rat organs and body based on the TISSUES database.
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