PMID- 30659235
OWN - NLM
STAT- MEDLINE
DCOM- 20200928
LR  - 20221122
IS  - 1476-5403 (Electronic)
IS  - 1350-9047 (Print)
IS  - 1350-9047 (Linking)
VI  - 26
IP  - 10
DP  - 2019 Oct
TI  - The mitochondrial retrograde signaling regulates Wnt signaling to promote 
      tumorigenesis in colon cancer.
PG  - 1955-1969
LID - 10.1038/s41418-018-0265-6 [doi]
AB  - Cancer cells are known to upregulate aerobic glycolysis to promote growth, 
      proliferation, and survival. However, the role of mitochondrial respiration in 
      tumorigenesis remains elusive. Here we report that inhibition of mitochondrial 
      function by silencing TFAM, a key transcription factor essential for 
      mitochondrial DNA (mtDNA) replication and the transcription of mtDNA-encoded 
      genes, markedly reduced tumor-initiating potential of colon cancer cells. 
      Knockdown of TFAM significantly decreased mitochondrial respiration in colon 
      cancer cells; however, the cellular levels of ATP remained largely unchanged as a 
      result of increased glycolysis. This metabolic alteration rendered cancer cells 
      highly susceptible to glucose deprivation. Interestingly, upregulation of 
      glycolysis was independent of hypoxia-inducible factor-1 (HIF1) as TFAM knockdown 
      cells fail to stabilize HIF1alpha under hypoxic conditions. Moreover, knockdown of 
      TFAM results in decreased expression of genes-associated cancer stem cells 
      downstream of Wnt/beta-catenin signaling. Metabolic analysis reveals that the level 
      of alpha-ketoglutarate (alpha-KG) was significantly upregulated in TFAM knockout cells. 
      Silencing of prolyl hydroxylase domain-containing protein 2 (PHD2), a 
      alpha-KG-dependent dioxyenase, rescued the expression of target genes of both HIF1alpha 
      and Wnt/beta-catenin. Furthermore, intestinal-specific knockout of TFAM prevents 
      tumor formation in Apc-mutant mouse models of colon cancer. Taken together, our 
      findings identify a novel role of mitochondria-mediated retrograde signaling in 
      regulating Wnt signaling and tumor initiation in colon cancer.
FAU - Wen, Yang-An
AU  - Wen YA
AD  - Markey Cancer Center, University of Kentucky, Lexington, KY, 40536-0509, USA.
FAU - Xiong, Xiaopeng
AU  - Xiong X
AD  - Markey Cancer Center, University of Kentucky, Lexington, KY, 40536-0509, USA.
FAU - Scott, Timothy
AU  - Scott T
AD  - Markey Cancer Center, University of Kentucky, Lexington, KY, 40536-0509, USA.
FAU - Li, Austin T
AU  - Li AT
AD  - Paul Laurence Dunbar High School, Lexington, KY, 40513, USA.
FAU - Wang, Chi
AU  - Wang C
AD  - Markey Cancer Center, University of Kentucky, Lexington, KY, 40536-0509, USA.
FAU - Weiss, Heidi L
AU  - Weiss HL
AD  - Markey Cancer Center, University of Kentucky, Lexington, KY, 40536-0509, USA.
FAU - Tan, Li
AU  - Tan L
AD  - Markey Cancer Center, University of Kentucky, Lexington, KY, 40536-0509, USA.
FAU - Bradford, Emily
AU  - Bradford E
AD  - Division of Digestive Diseases and Nutrition, Department of Internal Medicine, 
      University of Kentucky, Lexington, KY, 40536-0509, USA.
FAU - Fan, Teresa W M
AU  - Fan TWM
AD  - Markey Cancer Center, University of Kentucky, Lexington, KY, 40536-0509, USA.
AD  - Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, 
      KY, 40536-0509, USA.
FAU - Chandel, Navdeep S
AU  - Chandel NS
AD  - Department of Medicine, Northwestern University Feinberg School of Medicine, 
      Chicago, IL, 60611, USA.
FAU - Barrett, Terrence A
AU  - Barrett TA
AD  - Division of Digestive Diseases and Nutrition, Department of Internal Medicine, 
      University of Kentucky, Lexington, KY, 40536-0509, USA.
FAU - Gao, Tianyan
AU  - Gao T
AD  - Markey Cancer Center, University of Kentucky, Lexington, KY, 40536-0509, USA. 
      tianyan.gao@uky.edu.
AD  - Department of Molecular and Cellular Biochemistry, University of Kentucky, 
      Lexington, KY, 40536-0509, USA. tianyan.gao@uky.edu.
LA  - eng
GR  - R35CA197532/U.S. Department of Health & Human Services | NIH | National 
      Cancer Institute (NCI)/International
GR  - U24DK097215/U.S. Department of Health & Human Services | NIH | National 
      Cancer Institute (NCI)/International
GR  - P30CA177558/U.S. Department of Health & Human Services | NIH | National 
      Cancer Institute (NCI)/International
GR  - P30 CA177558/CA/NCI NIH HHS/United States
GR  - R01CA133429/U.S. Department of Health & Human Services | NIH | National 
      Cancer Institute (NCI)/International
GR  - U24 DK097215/DK/NIDDK NIH HHS/United States
GR  - R01 CA133429/CA/NCI NIH HHS/United States
GR  - R35 CA197532/CA/NCI NIH HHS/United States
GR  - R01 DK095662/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190118
PL  - England
TA  - Cell Death Differ
JT  - Cell death and differentiation
JID - 9437445
SB  - IM
MH  - Animals
MH  - Carcinogenesis
MH  - Colonic Neoplasms/*genetics
MH  - Humans
MH  - Mice
MH  - Mitochondria/*metabolism
MH  - Signal Transduction
MH  - Wnt Signaling Pathway/*genetics
PMC - PMC6748256
COIS- The authors declare that they have no conflict of interest.
EDAT- 2019/01/20 06:00
MHDA- 2020/09/29 06:00
PMCR- 2020/10/01
CRDT- 2019/01/20 06:00
PHST- 2018/06/25 00:00 [received]
PHST- 2018/12/17 00:00 [accepted]
PHST- 2018/11/30 00:00 [revised]
PHST- 2019/01/20 06:00 [pubmed]
PHST- 2020/09/29 06:00 [medline]
PHST- 2019/01/20 06:00 [entrez]
PHST- 2020/10/01 00:00 [pmc-release]
AID - 10.1038/s41418-018-0265-6 [pii]
AID - 265 [pii]
AID - 10.1038/s41418-018-0265-6 [doi]
PST - ppublish
SO  - Cell Death Differ. 2019 Oct;26(10):1955-1969. doi: 10.1038/s41418-018-0265-6. 
      Epub 2019 Jan 18.