Peroxisome from the protein-drug interaction point of view

Peroxisome proliferator-activated receptors (PPARs)
are categorized as orphan members of the nuclear receptor superfamily. Till
date, PPAR?, ?/?, ? are the three characterized subtypes of PPAR. The subtypes
have been shown to play critical roles in diseases such as obesity, diabetes,
atherosclerosis, and cancer. Its involvement in inflammatory processes31 is among the most studied roles of PPAR. Among the
subtypes, PPAR? and PPAR? are the most studied ones in inflammatory processes
whereas the role of PPAR? is yet to be elucidated. One of the factors that make
PPARs an interesting target of study is the loss-and-gain-of-function mutations
of PPAR? that have been studied in primarily insulin resistant diabetes32, or type-2 diabetes mellitus. Furthermore, from the
protein-drug interaction point of view PPARs are yet again an important targets
due to their well deliberated study with drugs. For instance, Thiazolidinedione
(TZD) is one of the drugs whose effect on PPARs has been well implicated, where
it activates PPAR? by altering expression of adipokines, restoring insulin
sensitivity to tissue, and upregulating free fatty acid uptake by adipocytes. However,
it is pertinent that the effect of other drugs on PPARs and their change in mechanism
should be dwelled upon; especially because this subtype is involved in a number
of other disease conditions including breast cancer. In breast cancer, PPAR?
ligands inhibit proliferation and induce apoptosis both in vitro and in vivo. Moreover,
the mechanism of action of the thiazolidinediones in breast cancer cells is not
fully understood but involves interactions with other nuclear hormone
receptors, transcriptional co-activators and repressors as well as PPAR? -independent
effects. Additionally, it has been shown that NFkB, a key transcriptional
factor involved in inflammation disease processes by blocking gene
transcription machinery from binding the promoter site33 is negatively regulated by PPAR?. Since NFkB is
clinically known to increase tumor cell invasiveness as a result of increased
uPA expression, the ability of PPAR? to inhibit NFkB expression is important in
breast cancer progression34. In addition to inhibiting NFkB expression, PPAR?
activation is also shown to downregulate transcription of the insulin receptor
(IR) by physically interacting with the transcription factors Sp1, C/EBP ?, and
AP1 in vitro, preventing IR transcription35. Furthermore, implications of insulin receptor
signalling has been shown in a number of neoplastic processes including
proliferation, invasion, and cell survival36. Adding to the evidences that insulin resistance is
associated with increased risk of breast cancer37 and poor patient prognosis38, elevated levels of insulin in newly diagnosed breast
cancer patients were shown to be related to an underlying insulin resistance39.These studies suggest that there is substantial
amount of data pertaining to association of diabetes with breast cancer40, however, there is no solid understanding of its
function. In our proposed project study, we strive to find relevant answers by
using our computational approach to analyse the significance of the drugs in
these aggressive diseases. It should be noted that where PPAR? is the most
studied subtype of PPARs with little evidences of PPAR? in inflammatory
processes, PPAR? has no such studies to report to. As a result, it becomes
imperative to perform a combined study of these PPAR
subtypes to understand their complete mechanism of action in association
between breast cancer and diabetes.