Now from the recent article by Chen et al we have the
following:
Lipids, either endogenously synthesized or exogenous,
have been linked to human cancer. Here we found that PML is frequently
co-deleted with PTEN in metastatic human prostate cancer (CaP).
We demonstrated that conditional inactivation of Pml in
the mouse prostate morphs indolent Pten-null tumors into lethal metastatic
disease. We identified MAPK reactivation, subsequent hyperactivation of an
aberrant SREBP pro-metastatic lipogenic program, and a distinctive lipidomic
profile as key characteristic features of metastatic Pml and Pten double-null
CaP.
Furthermore, targeting SREBP in vivo by fatostatin blocked
both tumor growth and distant metastasis. Importantly, a high-fat diet (HFD)
induced lipid accumulation in prostate tumors and was sufficient to drive
metastasis in a non-metastatic Pten-null mouse model of CaP, and an SREBP
signature was highly enriched in metastatic human CaP.
Thus, our findings uncover a pro-metastatic lipogenic
program and lend direct genetic and experimental support to the notion that a
Western HFD can promote metastasis.
Now what is the function of SREBP?
SREBP[1]:
In mammals, the transcription of several crucial genes required for lipid
synthesis is activated by a small family of transcription factors called SREBPs
(sterol response element binding proteins). A remarkable feature of SREBPs is
that their entry into the nucleus depends on their release from the membrane by
proteolysis (see the figure). During their synthesis, SREBPs are inserted into
the membrane of the endoplasmic reticulum, a membranous network in the cytoplasm
of the cell. In the endoplasmic reticulum, SREBPs form a complex with a membrane-embedded
protein called SCAP, which escorts the SREBPs to another cellular compartment
called the Golgi apparatus. Here, the SREBPs are sequentially cleaved by two
Golgi-specific proteases, releasing a soluble fragment from the amino terminus.
This fragment is a transcription factor, which, as a result of cleavage, is
free to migrate to the nucleus, where it activates the expression of genes
involved in the synthesis of cholesterol and fatty acids. Homeostasis is
achieved by a negative feedback loop in which cholesterol and fatty acids block
the proteolytic release of SREBPs from Golgi membranes. Interestingly, one of
the SREBPs (SREBP-1c) is subject to an additional regulatory step that takes
place at the promoter for SREBP-1c itself. Fatty acids, the end products of the
SREBP-1c pathway, inhibit the action of a transcription factor called LXR,
which is required for optimal expression of the SREBP-1c gene.[2]
As Brown and Goldstein note:
As an end-product repressor, cholesterol presents a
special problem because it is an insoluble lipid that resides almost
exclusively in cell membranes. How does the cell sense the level of a
membrane-embedded lipid, and how is that information transmitted to the nucleus
to regulate transcription? Answers are emerging from studies of a novel family
of membrane-bound transcription factors called sterol regulatory element
binding proteins (SREBPs) that regulate multiple genes involved in cholesterol
biosynthesis and uptake.
Here we review the SREBPs, focusing on the novel way in
which sterols regulate their proteolytic release from membranes. Remarkably,
insight into this processing may teach us about Alzheimer's disease, the most
common degenerative disease of the brain, as well as coronary artery disease,
the most common degenerative disease of the heart. Other aspects of SREBP
physiology, such as the DNA binding activities and interactions with other
transcription factors…
As Lewis et al note:
In recent years several reports have linked mTORC1
(mammalian target of rapamycin complex 1) to lipogenesis via the SREBPs
(sterol-regulatory-element-binding proteins). SREBPs regulate the expression of
genes encoding enzymes required for fatty acid and cholesterol biosynthesis.
Lipid metabolism is perturbed in some diseases and SREBP target genes, such as
FASN (fatty acid synthase), have been shown to be up-regulated in some cancers.
We have previously shown that mTORC1 plays a role in
SREBP activation and Akt/PKB (protein kinase B)-dependent de novo lipogenesis.
Our findings suggest that mTORC1 plays a crucial role in the activation of
SREBP and that the activation of lipid biosynthesis through the induction of
SREBP could be part of a regulatory pathway that co-ordinates protein and lipid
biosynthesis during cell growth.
In the present paper, we discuss the increasing amount of
data supporting the potential mechanisms of mTORC1-dependent activation of
SREBP as well as the implications of this signalling pathway in cancer.
From Sengupta et al we have the following Figure:
From Porstmann et al we have the following Figure which
demonstrates a more complete metabolic set of interactions:
Now one also notes that there is a significant relationship
also to the actions of the immune system. As Weichhart et al note:
Accumulating evidence suggests that innate immune cells
also actively control metabolic processes to adapt and optimize their effector
functions. These various effector functions are supported by an adaptation of
energy metabolism to accommodate their metabolic needs and link their
metabolism to the availability of nutrients. The mTOR network is a central
regulator of many core metabolic processes. Activation of mTORC1 usually drives
an anabolic response through hypoxia-inducible factor 1α (HIF1α), peroxisome
proliferator-activated receptor-γ (PPARγ), sterol regulatory element-binding
proteins (SREBPs) and MYC that induces the synthesis of nucleic acids, proteins
and lipids. In addition, it drives processes such as glycolysis and
mitochondrial respiration to provide the cellular energy and building blocks
for these responses. mTORC2 also enhances glycolytic metabolism by activating
AKT and promoting an inactivating phosphorylation of class IIa histone deacetylases.
This leads to the acetylation and inactivation of forkhead box protein O1
(FOXO1) and FOXO3, which in turn activates MYC transcription.
From Weichhart et al we have the following Figure demonstrating
the impact on the immune system:
The above immune interaction is a critical element in
understanding the cross reaction of the control of metabolic genes perhaps for
malignancy control and the operation of the immune system. It raises the
question perhaps of unintended consequences.
Now we also have the overall control element of p53. As Parrales
and Iwakuma note:
Mechanistically, mutant p53 binds to and activates SREBP,
crucial transcription factors that regulate transcription of several enzymes
involved in the mevalonate pathway, leading to enhanced prenylation of proteins
associated with cancer progression and activation of prenylated proteins in
breast cancer cells; hence, inhibition of protein prenylation by statins leads
to reduced malignancy of human breast cancer cells.
Importantly, the presence of p53 mutation correlates with
high expression of sterol biosynthesis genes in human breast tumors.
Additionally, since nuclear localization and activation of the YAP and TAZ
proto-oncogenes are regulated by prenylation and activation of Rho GTPases, statins
could also suppress progression of mutant p53-expressing tumors by inhibiting
YAP/TAZ activation by reducing protein prenylation of Rho GTPases, which is
promoted by SREBP and its cofactor mutant p53.
Now the second element in the Chen et al system is PML. PML is
characterized by NCBI as follows:
PML[3]:
The protein encoded by this gene is a member of the tripartite motif (TRIM)
family. The TRIM motif includes three zinc-binding domains, a RING, a B-box
type 1 and a B-box type 2, and a coiled-coil region. This phosphoprotein
localizes to nuclear bodies where it functions as a transcription factor and
tumor suppressor. Its expression is cell-cycle related and it regulates the p53
response to oncogenic signals. The gene is often involved in the translocation
with the retinoic acid receptor alpha gene associated with acute promyelocytic
leukemia (APL). Extensive alternative splicing of this gene results in several
variations of the protein's central and C-terminal regions; all variants encode
the same N-terminus. Alternatively spliced transcript variants encoding
different isoforms have been identified.
Also from Genecards[4]:
Functions via its association with PML-nuclear bodies
(PML-NBs) in a wide range of important cellular processes, including tumor
suppression, transcriptional regulation, apoptosis, senescence, DNA damage
response, and viral defense mechanisms. Acts as the scaffold of PML-NBs
allowing other proteins to shuttle in and out, a process which is regulated by
SUMO-mediated modifications and interactions. Isoform PML-4 has a multifaceted
role in the regulation of apoptosis and growth suppression: activates RB1 and
inhibits AKT1 via interactions with PP1 and PP2A phosphatases respectively,
negatively affects the PI3K pathway by inhibiting MTOR and activating PTEN, and
positively regulates p53/TP53 by acting at different levels (by promoting its
acetylation and phosphorylation and by inhibiting its MDM2-dependent
degradation).
From a recent paper by Guan and Kao the authors provide a
detailed overview of PML. They state:
The tumor suppressor protein, promyelocytic leukemia
protein (PML), was originally identified in acute promyelocytic leukemia due to
a chromosomal translocation between chromosomes 15 and 17. PML is the core
component of subnuclear structures called PML nuclear bodies (PML-NBs), which
are disrupted in acute promyelocytic leukemia cells. PML plays important roles
in cell cycle regulation, survival and apoptosis, and inactivation or
down-regulation of PML is frequently found in cancer cells. More than 120
proteins have been experimentally identified to physically associate with PML,
and most of them either transiently or constitutively co-localize with PML-NBs.
These interactions are associated with many cellular processes, including cell
cycle arrest, apoptosis, senescence, transcriptional regulation, DNA repair and
intermediary metabolism. Importantly, PML inactivation in cancer cells can
occur at the transcriptional-, translational- or post-translational- levels.
However, only a few somatic mutations have been found in cancer cells. A better
understanding of its regulation and its role in tumor suppression will provide
potential therapeutic opportunities. In this review, we discuss the role of PML
in multiple tumor suppression pathways and summarize the players and stimuli
that control PML protein expression or subcellular distribution.
The authors demonstrate the many pathway control and
interaction functions that PML is involved in. Specifically:
1. DNA Damage Repair: This is accomplished via a complex set
of interactions.
2. Transcriptional repression: This is done via a
sequestration of the RB and E2Fs blockage.
3. Transcriptional Activation: This is via STAT1 and NF-kB
activation amongst others.
4. AKT Pathway: This is via activation of PP2a, PTEN and
eIF4e
5. p53 pathway: via SIRTq, MAPK1, HAUSP, and MDM2
6. Epigenetic Regulation: The various HDAC, SIRT, and EZH2.
are just a few the authors present in their Figure 4.
PML appears to Chen et al as a key element in the
development of metastasis. It putatively also represents a therapeutic target.
Overall p53 and metabolism are intertwined and PML has that
role in the regulation of p53. From Flotter et al we have the detailed dynamics.
Flotter et al note:
Tumour development is accompanied by changes in cellular
metabolic activity, which allows cancer cells to grow and proliferate under
adverse conditions. The influence of p53 on cellular metabolism is complex and
involves multiples nodes of regulation. p53 changes the activity of multiple
metabolic pathways, including glycolysis, mitochondrial oxidative
phosphorylation and fatty acid synthesis via transcriptional and
non-transcriptional regulation. In addition, p53 governs the adaptation of
cancer cells to nutrient and oxygen deprivation, which is crucial for the survival
under the metabolically compromised conditions shaped by the tumour
microenvironment. Importantly, it has been shown that the regulation of
metabolic activity is essential to the tumour suppressive function of p53
Finally Chen at al conclude:
Our data provide a strong genetic foundation elucidating
the mechanisms underlying metastatic progression, and they demonstrate how
environmental dietary factors can boost progression from primary to metastatic
cancer, intertwining with the genetic makeup of cancer.
We demonstrated that SREBP- dependent lipogenesis, which
can be hyperactivated by concomitant activation of the PI3K-AKT and MAPK
pathways, or a HFD regimen, functions as an underlying rheostat toward
metastatic cancer progression.
Furthermore, we identified PML as a critical mediator of
feedback inhibition of MAPK signaling and lipogenesis, and its inactivation
propels metastatic progression in cancers driven by PTEN loss and PI3K- AKT
activation.
…Numerous mechanisms have been proposed to explain a
possible association between dietary lipids and CaP67, including paracrine
mechanisms through secreted cytokines from adipose tissues, endocrine
mechanisms through alteration of androgen levels and an induction of
basal-to-luminal cell differentiation caused by immune-cell infiltration.
However, we showed here that specific genetic perturbations or a HFD are
probably able to exert a direct effect on metastasis through increased lipid
accumulation.
We also characterized the intracellular lipid changes in
GEMMs of CaP and detected qualitative changes in four different lipid classes
as well as in the saturation of fatty acyl chains. Together, these results
established a strong mechanistic and causal link among aberrant lipogenesis,
excess lipid accumulation and metastasis, thus providing a compelling rationale
for integrating lifestyle data (for example, diet) and tumor genetics into
clinical practice to identify patients at high risk of metastasis.
Additionally, lipid metabolism itself is an attractive
therapeutic target through inhibition of lipogenic enzymes. Notably, such
inhibition decreases CaP cell viability only in the absence of an exogenous
lipid source such as lipoprotein, thereby highlighting the importance of
integrating pharmacologic approaches with stringent dietary regimens to prevent
metastasis. Future studies are warranted to evaluate whether specific lipid
subsets/signatures may serve as prognostic biomarkers to distinguish CaP with
metastatic potential from indolent disease.
Finally, given that PML is lost in human cancer of
multiple histological origins, our study suggests that PML loss may underlie
MAPK activation in cancers lacking genetic alterations in MAPK-signaling
components. …
This finding has equally important implications for
tumorigenesis, because PML loss in the hypoxic core or tumoral lesions not only
would activate mTOR, thus resulting in sustained HIF-1 activation, but also
would relieve the feedback inhibition of MAPK signaling triggered by mTOR
activation, thereby leading to simultaneous activation of both mTOR and MAPK
signaling.
Together, our results provide a potential roadmap for
targeted therapies tailored to individual patients for the prevention and
treatment of metastatic cancer.
Thus is this proposal based upon the experimental
identification of PML warranting of a therapeutic targeting? Everything is
worth examining, yet the complexity of the interactions, especially with the
immune system raises some concern. Chen et al note in their paper:
…PML loss might represent cooperative predictors of
overall survival after prostatectomy. Tissue microarray (TMA) analysis was
performed in prostatectomy specimens from 144 men with primary CaP. Loss of
PTEN and/or PML was significantly correlated with disease progression. Complete
loss of PTEN and PML at the protein level occurred in 15% of the high-grade CaP
samples, but not in the low-grade CaP samples.
It is well known as to the effect of PTEN. Chen et al argue
for a pari passu positioning of PML.
This is an interesting result but it is a long way from any
therapeutic targeting. The complexity of the PNL signalling does imply a
complex set of unintended consequences that must be explored.
References
1. Brown and Goldstein, The SREBP Pathway: Regulation of
Cholesterol Metabolism by Proteolysis of a Membrane-Bound Transcription Factor,
Cell, Vol. 89, 331–340, May 2, 1997
2. Chen et al, An aberrant SREBP-dependent lipogenic program
promotes metastatic prostate cancer, Nature Genetics (2018)
3. Flotter et al, Regulation of Metabolic Activity by p53, Metabolites
2017, 7, 21
4. Guan and Kao, The function, regulation and therapeutic implications
of the tumor suppressor protein, PML, Cell Biosci (2015) 5:60
5. Lewis et al, Regulation of the SREBP transcription factors by
mTORC1, Biochem. Soc. Trans. (2011) 39, 495–499;
6. Nohturfft and Losick, Fats, Flies, and Palmitate, Science Vol
296 3 May 2002 857
7. Parrales and Iwakuma, Targeting Oncogenic Mutant p53 for Cancer
Therapy, Frontiers in Oncology December 2015 | Volume 5 | Article 288 Review published:
21 December 2015 doi: 10.3389/fonc.2015.00288
8. Porstmann et al, A new player in the orchestra of cell growth:
SREBP activity is regulated by mTORC1 and contributes to the regulation of cell
and organ size, Biochemical Society Transactions (2009) Volume 37, part 1
9. Sengupta et al, Regulation of the mTOR Complex 1 Pathway by
Nutrients, Growth Factors, and Stress, Molecular Cell 40, October 22, 2010
10. Weichhart et al, Regulation of innate immune cell function by
mTOR, Nature Reviews Immunology 15, 599–614 (2015)
Posts
