Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
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Drug
Enzyme
Compound
Query: UMLS:C0699790 (
colon cancer
)
28,837
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The inositol pyrophosphates 5-InsP
7
(diphosphoinositol pentakisphosphate) and 1,5-InsP
8
(bis-diphosphoinositol tetrakisphosphate) are highly energetic cellular signals interconverted by the diphosphoinositol pentakisphosphate kinases (PPIP5Ks). Here, we used CRISPR to KO PPIP5Ks in the HCT116
colon cancer
cell line. This procedure eliminates 1,5-InsP
8
and raises 5-InsP
7
levels threefold. Expression of p53 and p21 was up-regulated; proliferation and G1/S cell-cycle transition slowed. Thus, PPIP5Ks are potential targets for tumor therapy. Deletion of the PPIP5Ks elevated [ATP] by 35%; both [ATP] and [5-InsP
7
] were restored to WT levels by overexpression of PPIP5K1, and a kinase-compromised PPIP5K1 mutant had no effect. This covariance of [ATP] with [5-InsP
7
] provides direct support for an energy-sensing attribute (i.e., 1 mM
K
m
for ATP) of the 5-InsP
7
-generating inositol hexakisphosphate kinases (IP6Ks). We consolidate this conclusion by showing that 5-InsP
7
levels are elevated on direct delivery of ATP into HCT116 cells using liposomes. Elevated [ATP] in
PPIP5K
-/-
HCT116 cells is underpinned by increased mitochondrial oxidative phosphorylation and enhanced glycolysis. To distinguish between 1,5-InsP
8
and 5-InsP
7
as drivers of the hypermetabolic and p53-elevated phenotypes, we used
IP6K2
RNAi and the pan-IP6K inhibitor,
N
2-(
m
-trifluorobenzyl),
N
6-(
p
-nitrobenzyl) purine (TNP), to return 5-InsP
7
levels in
PPIP5K
-/-
cells to those of WT cells without rescuing 1,5-InsP
8
levels. Attenuation of IP6K restored p53 expression but did not affect the hypermetabolic phenotype. Thus, we conclude that 5-InsP
7
regulates p53 expression, whereas 1,5-InsP
8
regulates ATP levels. These findings attribute hitherto unsuspected functionality for 1,5-InsP
8
to bioenergetic homeostasis.
...
PMID:KO of 5-InsP
7
kinase activity transforms the HCT116 colon cancer cell line into a hypermetabolic, growth-inhibited phenotype. 2907 69
