Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:2.7.11.2 (
PDK1
)
2,238
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Background:
The leading cause of poor prognosis in colorectal cancer (CRC) is the presence of colorectal cancer-initiating cells (CCICs). The interplay between the tumor microenvironment (TME) and CRC cells induces reacquisition of initiating cell characteristics, but the underlying mechanisms remain elusive.
Methods:
Candidate molecules were screened by global differential cDNA expression profiles of CCICs, which were enriched from patient-derived tumor xenograft models. Luciferase reporters and chromatin immunoprecipitation assays were used to explore the mechanism of TME factors regulating the transcription of
ANKRD22
. The effects of
Ankyrin repeat domain-containing protein 22
(
ANKRD22
) on energy metabolism were monitored by extracellular flux and
13
C-based metabolic flux analysis. Mass spectrometry was used to identify the interacting partners of
ANKRD22
. Morphological changes of CCICs overexpressing
ANKRD22
were observed by electron microscopy. The effects of
ANKRD22
on mitochondrial lipid metabolism were analyzed by lipidomics.
Results:
We identified a novel nucleus-encoded mitochondrial membrane protein,
ANKRD22
, which was upregulated in CCICs. We found that
ANKRD22
was induced by the p38/MAX pathway activated by different TME stimuli. As a key transcription factor, MAX promoted the transcription of
ANKRD22
. Expression of
ANKRD22
promoted glycolysis associated with a decrease in ATP/ADP and an increase in AMP/ATP levels, which were related to its interaction with
pyruvate dehydrogenase kinase
isoform 1 (PDK1) and multiple subunits of ATP synthase. Further, in CCICs,
ANKRD22
cooperated with the lipid transport protein, Extended Synaptotagmin-1 (E-Syt1), to transport excess lipids into mitochondria and reduced the number of mitochondria in an autophagy-independent manner, thus meeting the metabolic requirements of CCICs.
Conclusion:
ANKRD22
induced by TME promotes the metabolic reprogramming of CRC cells. Our study has identified
ANKRD22
/E-Syt1 as a potential target for eradicating CCICs.
...
PMID:ANKRD22, a novel tumor microenvironment-induced mitochondrial protein promotes metabolic reprogramming of colorectal cancer cells. 3190 35
