- A signaling
circuit that is continuously activated without the need for a ligand in
drug resistant prostate cancer patients has been
identified by research team from Scripps Institute.
- The molecules in
the signaling pathway can be targeted as potential therapy for people with
drug resistant prostate cancer.
- This overcomes
immunosuppression that would occur if NF-κB was targeted.
Research team lead by
assistant professor Jun-Li Luo has identified a signaling circuit which is
responsible for the resistance to therapy in prostate cancer. When the factors
involved in the signaling circuit were targeted, it suppressed the advancement
of prostate cancer development.
Finding a New Way to
Treat Prostate Cancer
The method of treatment
for prostate cancer is based on starving the cancer cells which involves
depriving the cells of testosterone. Though this is found to be effective
initially, most patients soon develop a resistance to this method of treatment.
There are no other known methods of treatment for prostate cancer, therefore,
the development of resistance to this therapy is catastrophic.
‘The new targets could provide an effective recourse for people with drug resistant prostate cancer’
The current study by the
research team from Scripps Medical Centre identified a
signaling circuit that remains constitutively active. The pathway does not
require any ligand to activate it but it remains continuously active.
is known to be the second most type
of cancer among men but early detection and care will aid in treating the
condition successfully. There are more than 2 million prostate cancer survivors
in the U.S.
Most prostate cancers
are adenocarcinomas and they can grow and spread rapidly but most of them are
very slow to grow. According to recent studies, the number of prostate cancer
incidences is rising in India. It is a major health problem in the
industrialized world. However, contrary to previous reports that prostate
cancer incidence is low in India, recent studies have shown a sharp increase.
This is due to large spread migration of the rural population to the cities
with changing lifestyle, alterations in the dietary pattern, greater awareness
about the disease, better medical facility and diagnosis.
The increasing numbers
of prostate cancer warrant an alternate treatment method, which the current
study could offer. Resistance to the current method of treatment is a major
hindrance to care, resulting in poor prognosis. The study that focuses on
understanding the mechanism behind the resistance and identifies key targets
for drug therapy could provide a better model of care.
Composition of the
composed of the protein complex IκBα/NF-κB (p65) along with several other
molecules. The signaling circuit controls the stem cell transcription factor
expression which is responsible for the rapid growth of the cancer cells. These
are proteins that are involved in the change from DNA to RNA.
Normally a ligand or a
binding factor would be required for activation but the absence of any ligand
and the constitutive activation of the NF-kB circuit is a potential target for
drug therapy, according to Dr. Luo.
Molecules in the Signaling Circuit
NF-kB are a group of
closely related dimers that bind to the common site kB. These are transcription
factors that are sequence specific and have long known to be involved in
inflammatory response. The importance of these transcription factors in
inflammation is undisputed but studies conducted recently on NF-kB as well as
the signaling pathways are associated with its activation as well as in tumor
Functions of NF-kB
property- NF-κB exhibits anti-apoptotic property that aid in protection
- They play a role
in maintaining inflammatory response via leukocyte activation.
- NF-κB promotes
apoptosis of leukocyte which in turn promotes the resolution of
- NF-κB is
associated with the feedback control of inflammation by a variety of means
which contribute to the size and durations of the inflammatory response.
NF-kB is considered to
be very important in the development of cancer, but its use as a target for
therapy is greatly compounded by the fact that there are serious side effects
associated with immunosuppression, which is caused due to the inhibition of
NF-kB in the non-cancerous immune cells.
Dr. Luo who is the
senior author of the current study found that the suppression of NF-kB in
non-cancerous immune cells could be avoided by targeting other molecular
components in the signaling pathway.
The Other molecular
components in the signaling pathway include
- The microRNA
miR-196b-3p- Promotes the development of tumor
- Meis2 - Essential
mammalian developmental gene. Overexpression of this gene could disrupt
- PPP3CC- It
inhibits the activity of NF-kB in prostate cancer cells.
The lead author of the
study Dr. Ji-Hak Jeong who is a TSRI research associate said that disrupting
this circuit using individual components of the circuit as targets could
prevent the expression of these transcription factors ' significantly impairs
therapy-resistant prostate cancer'. References:
- Ji-Hak Jeong, Sun-Jin Park, Shohreh Iravani Dickinson, Jun-Li Luo. A Constitutive Intrinsic Inflammatory Signaling Circuit Composed of miR-196b, Meis2, PPP3CC, and p65 Drives Prostate Cancer Castration Resistance.Molecular Cell,(2016)DOI: 10.1016/j.molcel.2016.11.034