Title:Signal Transduction through JAK-STAT and NF-κB Regulated Pim-1 Kinase: Novel Target for Anticancer Leads
VOLUME: 13 ISSUE: 2
Author(s):Sisir Nandi*, Mohd Salman, Ankita Sharma and Mohit Kumar
Affiliation:Division of Pharmaceutical Chemistry, Global Institute of Pharmaceutical Education and Research, Affiliated to Uttarakhand Technical University, Kashipur-244713, Division of Pharmaceutical Chemistry, Global Institute of Pharmaceutical Education and Research, Affiliated to Uttarakhand Technical University, Kashipur-244713, Division of Pharmaceutical Chemistry, Global Institute of Pharmaceutical Education and Research, Affiliated to Uttarakhand Technical University, Kashipur-244713, Division of Pharmaceutical Chemistry, Global Institute of Pharmaceutical Education and Research, Affiliated to Uttarakhand Technical University, Kashipur-244713
Keywords:Signal Transduction, Pim-1 Kinase, JAK, STAT3/5, NF-κB, Novel cancer targets, JAK-STAT inhibitors, NF-κB
inhibitors.
Abstract:Background: Signal transduction is a process where a chemical or physical signal is
transmitted from extracellular to the intracellular nuclear matrix as a series of molecular events,
most commonly protein phosphorylation which ultimately result in a response. At the molecular
level, such responses include changes in the transcription or translation of genes, and posttranslational
and conformational changes in proteins, as well as changes in their location. These
molecular events are the basic mechanisms of controlling cell growth, proliferation, metabolism
and many other processes. In multi-cellular organisms, signal transduction pathways evolve to
regulate cell communication in various ways. One of the important signal transduction occurs
through JAK-STAT and NF-κB regulated Pim-1 kinase expression.
Methods: Major pathways such as JAK-STAT and NF-κB signaling are involved as the targets of
Pim-1 kinase activities including cell cycle progression, mitotic cell division, oncogenic transcription,
apoptosis and metastatic invasion. There are three target points in JAK –STAT systems including
the inhibition of activated JAK via phosphorylation, STAT –STAT dimerization and the
entry of activated STAT components for nuclear binding. NF-κB signaling is regulated by IKK
enzyme proteasomal degradation and translocation of activated NF-κB complex into nuclear domain
for DNA transcription and cellular expression. A number of inhibitors were designed to inhibit
these major drug target points of activated JAK-STAT and NF-kB signaling cascades.
Results: Pim denotes Proviral insertion in murine. It was reported that a wide range of human
cancers including bladder cancer, colorectal cancer, head and neck cancer and hematological malignancies
such as leukemia and lymphomas form due to over-expression of PIM1 via JAK-STAT
and NF-κB signaling cascades. An attempt has been made in the present review to focus various
potent inhibitors for the inhibition of JAK-STAT and NF-κB signaling targets. These inhibitors
are in clinical trials or to be progressed in the clinical investigation.
Conclusion: Incorrect regulation of cytokine-mediated activation of JAK-STAT and NF-κB produces
abnormal expression of Pim -1 kinase and solid cancer. Phosphorylated JAKs can induce
transcription of target genes and NF-κB acts as a regulator of a gene that can control cell proliferation
and cell survival. Therefore, JAK-STAT and NF- κB regulated Pim-1 kinase is a novel target
for anticancer leads and these leads can be used to design a template as an anticancer agent. Further
clinical studies can be carried out to discover new novel congeneric entities.
