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CONTRIBUTION OF JAK-STAT SIGNALING PATHWAYS AND
NOVEL APPROACHES IN SITE SPECIFIC DRUG DELIVERY FOR
MALIGNANT TUMOURS: A SYSTEMATIC OVERVIEW
Snehal Gajanan Shinde*
Final year B. Pharmacy of Shree Saraswati Institute of Pharmacy, Tondavali, Kankavali,
Sindhudurg, Maharashtra.
Dr. Babasaheb Ambedkar Technological University, Lonere, Raigad, Maharashtra.
ABSTRACT
Cancer is prevalent cause of mortality around the world. As we know
JAK STAT signaling pathway regulates cellular processes like cell
division, cell death and immune regulation. They also control cell
survival, proliferation, differentiation and hematopoiesis. Aberrated
activation of JAK and STAT signaling pathway promote tumour
growth or tumorigenesis. Dysregulation of this signaling pathway also
cause numerous immune inflammatory diseases. As the JAK and
STAT3 play an important role in the signaling pathway is the target
strategy for intracellular drug development. The therapeutic approaches
like JAK and STAT inhibitor, natural agents including phytochemicals
which exhibit potent anti-cancer activity via various mechanisms are
mentioned in this topic. Based on comprehensive analysis of literature several chemical as
well as phytochemical exerts therapeutic and cancer preventive effect through regulation of
JAK and STAT signaling pathway. Future perspective related to preclinical and clinical
research is necessary to completely comprehend the capability of modulating JAK and STAT
signaling to achieve efficient cancer control and treatment. This topic includes structural
morphology of JAK and STAT domain, regulation signaling pathway of JAK and STAT,
pathological or aberrant signaling of JAK and STAT, effect of mutagen or mutative agent in
the JAK STAT signaling pathway, current approaches in the treatment of malignancy related to
JAK STAT and future strategies which control and prevent malignancy associated with JAK -
STAT signaling pathway.
WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
SJIF Impact Factor 7.632
Volume 10, Issue 7, 983-1001 Review Article ISSN 2278 – 4357
*Corresponding Author
Snehal Gajanan Shinde
Final year B. Pharmacy of
Shree Saraswati Institute of
Pharmacy, Tondavali,
Kankavali, Sindhudurg,
Maharashtra.
Article Received on
10 May 2021,
Revised on 30 May 2021,
Accepted on 20 June 2021
DOI: 10.20959/wjpps20217-19389
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KEYWORDS:- Malignancy, JAK-STAT, Signaling pathway, JAK mutation, STAT3
inhibitor, SBDD and computational drug design.
INTRODUCTION
Cancer or malignancy is a significant medical issue which driving mortality throughout the
world.[1] It is an uncontrolled or unscheduled cell multiplication or cell growth at the
particular part of body. Tumors associated with viral or bacterial infection and genetic
mutation are able to influence cancer growth rate.[2] Several risk factors such smoking,
chewing tobacco, alcohol, obesity, chronic inflammation, age, ethnicity and geographical
location will also contribute in development of cancer recent researches suggest the majority
of cancer are brought about by malfunction of numerous protein coded genes, such as anti-
apoptotic Proteins, growth factors, receptor of growth factors and transcript of factors.[3] This
factors also constitute as a target for cancer prevention and treatment .When tumors are
formed, their abnormal cells obtain at least 10 common characteristics that describe the
malignant tumor cell’s complexity, including proliferation, resistance to growth suppressors,
avoidance of programmed cell death (apoptosis), unlimited ability to replicate, growth of fresh
blood vessels, tissue invasion with risk of metastatic growth, genetic instability and mutation
of high frequency, tumor-driven inflammation, altered metabolism, and compromised
immunological surveillance.[4,5] During tumor advancement and malignant conversion,
abnormal cells evade the mechanisms of host defense. Targeting and inhibiting the previously
mentioned characteristics has been perceived as potential approaches to cancer treatment.
Apart from conventional treatment, an additional area of interest among researchers is the
utilization of alternative therapy, particularly using dietary sources to regulate these key
mechanisms.[6] The JAK and STAT are intracellular pathways connect signaling from
extracellular cytokines, hormone and growth factor with the nuclear transcription
machinery.[7] The cascade consists tyrosine kinase, transcriptional factors and different
regulatory proteins.[8]
JAK-STAT signaling control cellular responses, immune responses,
cell proliferation, cell migration, cell survival, cell apoptosis according to signal. These event
play crucial role in various biological functions such as hematopoiesis, immune development,
inflammatory responses, adipogenesis and angiogenesis.[9,10,11] Under normal physiological
conditions JAK STAT pathway is strictly regulated. However, in pathological state the
aberrant regulation of JAK STAT can cause cancer, atherosclerosis, rheumatoid arthritis,
diabetes, etc.[11] Generally increasing JAK mutation promotes STAT activation which
triggers tumorigenesis.[12] The prominence uses of JAK inhibitor mainly in the treatment of
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JAK mutation is one of the important aspect of treatment relief from
malignancy/cancer.[13,14,15,16]
Dysregulation of a protective mechanism or immune checkpoints used by a number of
malignancies to escape from the immune surveillance allowing for cancer development.[17]
This has inspired the idea of boosting the host immune response as an anti-cancer therapy. The
blockade of immune checkpoints such as programmed cell death 1 ligand 1 (PD-L1) and
cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) will remains untreatable.[18,19,20] In
order to expand the area of research of treatable cancers as well as increase the number of
patients that respond to the therapy, novel therapeutic targets and new molecules/strategies
should be urgently identified and developed for immunotherapy appropriate for the clinical
use.[21] The JAK/STAT pathway regulates embryonic development and is involved in the
control of processes such as stem cell maintenance, hematopoiesis and the inflammatory
response. The pathway transduces signals from cytokines, interleukins and growth factors that
act through a number of transmembrane receptor families.[22] These includes two types of
receptors as follows:
1) Type I receptors -
I. Erythropoietin receptor
II. Granulocyte colony stimulating factor (G-CSF)
2) Type II receptors -
I. Type IIa - Granulocyte-macrophage colony-stimulating factor
II. Type IIb - Interleukin-6 and leukemia inhibitory factor
These receptors are associated with inactive kinases called as JAK kinases intracellularly.[98]
Binding of ligand with receptor cause alteration in alignment of receptor associated JAK,
enable phosphorylation of specific tyrosine residues that convert inactive JAK to active
tyrosine kinase.[22] In some cases, STAT can be activated by receptor with intrinsic tyrosine
kinase activity such as epidermal growth factor receptor and platelet derived growth factor
receptor.[22]
JAKs (Janus kinases)
JAK protein-are non-receptor tyrosine kinase that are useful for activation of signaling
mediated by receptor for cytokine, hormone and several growth factor. This receptor includes
four proteins weighing 120-130k Da. This family of receptor includes JAK1, JAK2, JAK3 and
TYK2 with seven defined region of homology called JAK homology domain.[Fig. 1, 10] In
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this domain C terminal contains kinase and pseudo kinase connected to activation loop of
domain essential for JAK activation. The pseudo kinases domain act as catalyst.[23] The FH2
domain mediate JAK associated phosphorylation while N terminal called as FERM involved
in the associated between JAK and cytokine receptor.[23,24]
Figure 1: JAK Domain.[29]
STATs (Signal transducer and activator of transcription proteins)
The STAT family has seven members named as STAT1 toSTAT4, STAT5a STAT5b and
STAT6.This are light in weight approximately 80-100 k Da. The STAT domain contain 7
regions which includes N terminal domain, purple domain, DNA binding domain, SH2 domain
and a transactivation domain at C terminals.[12 Fig. 2] The N terminal is implicated in
STAT dimer-dimer and other protein interaction which is less conserved among Statute spiral
or coiled domain is responsible for protein-protein interaction.[11] The DNA binding domain
defines STAT dimer to recognize 8-10 base pair of DNA element. The SH2 domain is
responsible for specific tyrosine phosphorylated peptide sequences within binding molecule
for intracellular signaling function. The transactivation domain holds two amino acids (tyrosine
and serine) essential for STAT activity so that JAK can promote phosphorylation of tyrosine
which lead to STAT dimerization whereas STAT phosphorylated serine by MAPK (mitogen
activated protein kinases) which enhance transcriptional activity.[12,25] These all domain of
STAT essential for its biological functions to respond extracellular stimuli.
Figure 2: STAT Domain.[29]
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Signaling pathway of JAK/STAT
When external stimuli i.e. cytokine, growth factor binds to cellular membrane which activate
JAK associated receptor after auto phosphorylation of JAK. These triggers conformational
change in structure of JAK which binds to substrate and exert kinase activity.[Fig. 5] JAK
binding site then expose to cytoplasm where STAT recruited their area for phosphorylated
JAK. Due to this reaction single STAT monomer convert into homodimer i
e.STAT1,STAT3,STAT4, and STAT5a STAT5b or heterodimer i e.stat1-stat2 and stat1-
STAT3.[29] These active STAT dimer translocate into nucleus and binds to DNA lead to
activation of their target gene In the non-canonical signaling other tyrosine kinases different
from JAK can activate stat factor including epidermal growth factor (EGF) and platelet
derived growth factor (PDGF)and non- receptor tyrosine kinases (e.g.proto-oncogene tyrosine
kinase Src and Dcr-Abl).[8,11,35,97] STAT also having ability to form a dimer and exert
biological activity in absence of canonical JAK tyrosine phosphorylation. Some studies show
that JAK 2 can enter into nucleus and mediate modification in histone.[12,25]
Figure 3: JAK-STAT Signaling pathway.[99]
Regulation of JAK/STAT
The JAK/STAT pathway is regulated endogenously in tight and precise manner. Since,
dysregulation of JAK/STAT can lead to various pathological disorders including malignancies,
most of JAK/STAT modulators are assessed as interesting therapeutic approaches.[29] Most
common and conventional JAK/STAT modulators is protein tyrosine phosphatases (PTPs)
which negatively regulates JAK/STAT signaling pathway by dephosphorylating the associated
receptors of JAK and JAK itself. Another classical group of JAK/STAT negative modulators
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is protein inhibitors of activated STATs (PIAS). These proteins can inhibit STAT signaling
function directly by inhibiting attachment of STAT with DNA or indirectly inhibiting STAT
dimerization.[26,27] Furthermore, most studied family of negative modulators is suppressor of
cytokines signaling (SOCS) proteins.[28] It is a family of eight members consists SOCS 1-7 and
CIS. All members of this family shows different domain structure consists N-terminal domain,
central Src homology Region include extension of SH2 Sequence that leads to binding of SOCS
to tyrosine phosphorylated residue in JAK associated receptors and a C-terminal domain which
is also known as SOCS box.[30] The SOCS1-3 consists a small kinase inhibitory region (KIR)
near the N-terminal region which inhibits catalytic activity of JAK receptors. These family of
proteins work on base of negative feedback mechanism where activated STATs induce
expression of SOCS which controls STATs transduction signaling.[29] The suppression of
JAK/STAT signaling by SOCS include following mechanism:
Figure 4: JAK-STAT Regulation.[29]
Dysregulation/overactivity of JAK/STAT-
The multifactorial process of tumorigenesis is characterized by cellular failure in sensing and
repairing DNA damage, loss of regulation of cell cycle progression and apoptosis and
expression of aberrant pattern of growth signaling and angiogenesis.[31,32] Numerous studies
have strong evidence that JAK kinases play important role in cancer genesis and
progression.[33,34]
Overactivity or gain in function of JAK, cognate JAK tyrosine kinase or JAK
associate receptor leads to generation of fusion protein or the loss of negative feedback
regulation of JAK signaling which ultimately effect on the STAT signaling results into
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oncogenesis.[35] Recent studies discover that JAK point somatic mutation is a most common
cause for JAK dysregulation in the malignancy related to JAK2 mutation. Other JAK mutations
are associated to hematological malignancy and down syndrome, hence the discovery of potent
drug which avoid JAK proteins mutation is major approach of drug design in malignancy
related to JAK STAT dysregulation.[36,29]
Role of mutations - JAK1 mutation
It plays important role in lymphopoiesis. JAK1 activating mutations found in several lymphoid
neoplasms with highest frequency (7-25%)in T- ALL (T acute lymphoblastic leukemia) but
also in B- ALL and T cell prolymphocytic leukemia. It rarely found in acute myeloid leukemia
(AML).[14] Most of the JAK 1 mutations occurs within pseudo kinase domain. JAK1A634D
mutation in adult T-ALL leads to JAK 1 activation and results into overexpression of JAK 1
receptor. The somatic JAK 1 mutation cause modification in AML since they do not directly
induce cell transformation but modify activation of downstream signaling pathway in response
to external stimuli.[37,38]
JAK2 Mutation
Myeloproliferative disorders (MPD) are the group of chronic clonal malignancies arise from
expansion of matured hematopoietic progenitor cells.[39] These are of two types-
a) Chronic myelogenous leukemia (CML)-CML involved Philadelphia(Ph) chromosome
associated to BCR - ABL fusion oncoprotein.
b) Ph negative MPD Syndrome-These referred as polycythemia vera (PV), essential
thrombocythemia (ET) and idiopathic myelofibrosis (IMF).[40] These are caused due to
hypersensitivity of numerous cytokines. JAK2 single point somatic mutation at
chromosome 9p24, exon14 cause genetic abnormality in stem cell nature affect myeloid
lineage.[41,42]
JAK2V617F mutation effect on B lymphocytes and T lymphocytes will
cause Ph negative MPD's. This results into differentiation of stem cell origin in lymphoid
and myeloid.[43]
JAK3 mutation
JAK3 involved in lymphocytes development and carry out its function after interacting with
interleukin receptor. JAK3 mutation cause lymphoproliferative disorders.[44,45,46] JAK 3
mutation occurs at FERM domain and cause defect in gamma chain of receptor involved in
JAK 3 signaling pathway.[47] JAK3A572V mutation responsible for STAT 5 activation due to
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that pseudo kinase is negatively regulates which results into acute megakaryoblastic leukemia
(AMKL).[29] JAK3A572V and JAK3A573V mutation damage exon12 in JH2 domain will
cause non-Hodgkin lymphoma and natural killer/T-cell lymphoma (NKTCL)due to
overagrresion of natural killer/T lymphocytes.[45,48]
Novel approaches for site specific drug delivery in malignancies - JAK Inhibitors -
In 1996 AG490 JAK inhibitor had ability to treat recurrent B cell leukemia based on
experimental studies.[49] Since then natural components like Curcumin, lavoperidol have been
preclinical examine to inhibit anti-inflammatory pathway.[50] These pathways inhibit STAT3
phosphorylation through decrease production of cytokines after direct bind with JAK.[51,52] The
research says that JAK inhibitor and its development continue with discovery of driver
mutation and myeloproliferative leukemia virus oncogene that produce JAK 2 activation and
cause aberrant JAK STAT signaling.[53,54,55] JAK inhibitors classified into four different groups
depending upon their region of target as follows-
a) Type 1 Inhibitor-They target ATP binding site of JAK in active confirmation of kinase
domain.[56] These compounds are different according to their specificity. Most of JAK
inhibitors target JAK 1, JAK 2 and other kinases like TYK2 and JAK 3. Some of them
can inhibit all JAK (e.g. gandotinib) and less frequently they specifically target JAK 2 (e
g. pacritinib), JAK1(e.g. filgotinib) or JAK 3 (e.g. JANEX 1).[56,57,58] Type1 JAK 2
inhibitors are commonly use in MPN such as myelofibrosis, polycythemia vera, essential
thrombocythemia whereas type 1 JAK inhibitors target JAK 1 and JAK 3 used to treat
inflammation and autoimmune disease.[59,60,61,62,63]
b) Type 2 Inhibitors-Type 2 JAK2 inhibitors have been developed recently in which NVP-
BBT594 was effective in MPN.[64] Type 2 JAK 2 inhibitors are more powerful and
effective than Type 1 inhibitors. They target ATP binding pockets of kinase domain in
inactive conformation.[56]
c) Allosteric inhibitor -In this group of inhibitors there are two types of inhibitor which are
type 3 and type 4. Type 3 inhibitors binds to a site close to ATP binding site (e.g.LS104)
whereas type 4 inhibitors bind to Allosteric site distant from ATP binding site (e.g.
ON044580).[65,66]
since they do not target ATP pockets, they are more specific than Type 1
and type 2. hence this group of inhibitors particularly used in MPN related to JAK
mutation.[56]
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STAT Inhibitors
The main target for STAT inhibitors is STAT3 receptor which is an ideal binding site like
double stranded DNA for intratumoral or intravenous injection.it prevents STAT 3 dimer from
binding to its target by isolating into STAT3.[67,68,69,70] preclinical studies show that
phosphorylation of STAT3 cause due to STAT 3 decoy in neck and head squamous cell
carcinoma. The significant level of phosphorylated STAT3 result in cancer cell apoptosis,
results in lower tumor growth. Currently STAT 3 decoy is studied in patients with neck and
head cancer which is less intrusive and radially assessable with local injection.[6] Direct STAT
3 inhibitors are designed to influence SH2 domain by restricting STAT3 phosphorylation or
dimerization. STAT3 inhibitors such as peptidomymetics act by inhibiting phosphorylation of
STAT3 intracellularly, DNA binding and DNA transcription.[71] Peptidomymetics mainly
associated with monomeric proteins of stat 3 which are non-phosphorylated in nature via pY-
SH2 domain binding to create a complex which results into decrease amount of free non-
phosphorylated STAT3 monomer use in the phosphorylation and denovo activation. These
agents also use to decrease progression of cancer.[71,72,73] For example, nifuroxazide a drug
used to treat diarrhea could effectively use to inhibit JAK2 and TYK2 while it also uses in
decreasing the p-STAT3 level in multiple myeloma. The antimalarial drug named as
pyrimethamine also use as STAT 3 inhibitor and myeloma growth inhibitor to treat
lymphocytic leukemia hence tyrosine and non-tyrosine phosphorylated STAT3 performs a
significant role in cancer cell development and this knowledge can be used to develop a
potential anticancer agent.[74,75]
Phytochemicals inhibiting the JAK STAT Signaling pathway
Several bioactive photocompounds demonstrated that JAK STAT pathway is inhibited by
various mechanism. Phytochemicals can target more than one site of JAK STAT pathway.[6]
These agents can able to block signaling pathway by decreasing level of cytokines or growth
hormones which triggers JAK STAT protein activation. These can also act by stopping JAK
phosphorylation before STAT activation. JAK STAT signaling control can achieve by
inhibiting STAT dimerization and stop translocation of STAT dimer from cytoplasm to
nucleus.[76,77] This results into avoid STAT-DNA binding which directly inhibit JAK STAT
regulated gene transcription. These can be combine with JAK STAT pathway inhibitor such as
SHP (Src Homology 2 (SH2) domain containing protein tyrosine phosphatase). Recent
experiment shows that phytochemicals can specifically block one target site.[78,79]
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Table 1: Examples of phytoconstituents used in malignancies.[6]
Name Mechanism of action Anticancer effect
Curcumin STAT3 inhibition, decrease
gene expression
Lung cancer
T cell leukemia
Indirubin STAT3 inhibition Prostate and breast cancer
Ergosterol peroxide JAK2 inhibition Multiple myeloma
Dihydroartemisinin JAK2 and STAT3 inhibition Head and neck cancer , liver
cancer, colon cancer, tongue
cancer
β- caryophyllene oxide JAK1/2 and STAT3
inhibition
Multiple myeloma, prostate
and breast cancer
Future perspectives regarding to treatment of malignant tumours - Advances in Anti-
tumour therapeutics targeting STAT3 -
STAT3 is an essential for various cellular processes which including cell cycle, cell
proliferation, cell apoptosis and tumorigenesis. Normal cell STAT 3 activation is regulated to
prevent uncontrolled gene regulation while abnormal activation of STAT 3 results into
numerous disease development.[83] It also includes disease like cancer such as brain, lung,
pancreatic, renal, colorectal, endometrial, cervical, ovarian, breast and prostate cancer,
melanoma, glioma, head and neck squamous cell carcinoma, lymphoma and
leukemia.[80,81,82,83] Experimental studies say that STAT 3 inhibition will lead to decrease
growth of tumour and their progression.[84] STAT3 also inhibit synthesis of p53 will reduce
binding of STAT 3 with DNA receptor and decrease the probability of gene mutation. It
significantly reduces tolerance of ovarian cancer cell to stress and damage.[85] Research shows
that STAT3 activate miR-608 which inhibits proliferation, migration of lung cancer cell.[86]
Recently researcher have attempt to inhibit STAT3 signaling pathway as a method of cancer.
They also attempt to identify a small inhibitor molecule that directly bind SH2 domain of
STAT 3 which results into prevention of tyrosine phosphorylation, protein dimerization and
transcription activity.[87,88] Recently structure based drug design and computational docking
techniques are used for identification of smaller molecule. e.g. STA-21(deoxytetrangomycin)
which is an analogue of tetrangomycin (non-peptide small molecule STAT3 inhibitor) was
discovered using SBDD and successfully completed phase1/2 clinical trials. This will
inhibit malignant transformation, tumour cell proliferation, migration and invasion.[89,90]
Other small molecules of STAT 3 activation inhibitor under clinical trials are as follows:
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Table 2: Examples of STAT inhibitors.[96]
Inhibitor Name Mechanism Rx Disease
STA-21 SH2 domain inhibition Psoriasis
Pyrimethamine STAT3 inhibition Lymphocytic leukemia
OPB-51602 SH2 domain inhibition Nasopharyngeal carcinoma
Non-Hodgkin lymphoma
OPB-31121 SH2 domain inhibition Leukemia
Hepatocellular carcinoma Non-
Hodgkin lymphoma
Integrating STAT3 in combination cancer immunotherapy
Immunotherapy is currently most prominent approach in the treatment of cancer. This
therapeutic strategy represents as immune check point blockade (ICB) and chimeric antigen
receptor T-cell (CAR-T), as obtained unprecedented result in patient with previously incurable
cancer.[93,21] ICB shows remarkable effectiveness in Melanoma, lung cancer and renal
cancer.[91,92] The previous preclinical and clinical data says combination cancer
immunotherapy have enhanced therapeutic efficacy and reduce drug resistance compare with
monotherapy.[94,95]
Figure 5: combination cancer immunotherapy.[21]
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CONCLUSION
Cancer is a dangerous health risk for people worldwide. The morbidity and the mortality rates
connected with cancer are alarming, despite the existence of multiple treatment modalities for
patients suffering from this disease. JAK/STAT is a vital signaling pathway implicated in the
proliferation, differentiation, apoptosis, evasion, and survival of neoplastic cells. In addition,
its aberrant activation results in cancer-promoting mechanisms. A great effort has been made
by researchers in the last decade to find and characterize novel JAK and STAT3 inhibitors that
might be clinically used, and, in fact, some of them have already reached clinical evaluation.
However, further work is required to establish to what extent the observed activation of
JAK/STAT signaling is driving disease. This may determine the extent to which inhibition of
the pathway brings therapeutic benefits. The near future should see the transition of drugs
that inhibit JAK/STAT signaling from preclinical models into early phase clinical trials.
Targeting drugs that inhibit JAK/STAT activation to these groups of patients is likely to be
particularly promising.
ACKNOWLEDGEMENT
To the best of my knowledge, the material included in this topic is having original sources
which are appropriately Acknowledged and referred. I would like to express my sincere
gratitude to Mr. Chintan Davande student of shree saraswati institute of pharmacy, tondavli
and all teaching staff for their continous guidance, support and motivation.
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