PMID- 36388465
OWN - NLM
STAT- MEDLINE
DCOM- 20230731
LR  - 20230731
IS  - 2767-9764 (Electronic)
IS  - 2767-9764 (Linking)
VI  - 2
IP  - 10
DP  - 2022 Oct 10
TI  - Mitochondrial Matrix Protease ClpP Agonists Inhibit Cancer Stem Cell Function in 
      Breast Cancer Cells by Disrupting Mitochondrial Homeostasis.
PG  - 1144-1161
LID - 10.1158/2767-9764.CRC-22-0142 [doi]
AB  - Mitochondria are multifaceted organelles which are important for bioenergetics, 
      biosynthesis and signaling in metazoans. Mitochondrial functions are frequently 
      altered in cancer to promote both the energy and the necessary metabolic 
      intermediates for biosynthesis required for tumor growth. Cancer stem cells 
      (CSCs) contribute to chemotherapy resistance, relapse, and metastasis. Recent 
      studies have shown that while non-stem, bulk cancer cells utilize glycolysis, 
      breast CSCs are more dependent on oxidative phosphorylation (OxPhos) and 
      therefore targeting mitochondria may inhibit CSC function. We previously reported 
      that small molecule ONC201, which is an agonist for the mitochondrial 
      caseinolytic protease (ClpP), induces mitochondrial dysfunction in breast cancer 
      cells. In this study, we report that ClpP agonists inhibit breast cancer cell 
      proliferation and CSC function in vitro and in vivo. Mechanistically, we found 
      that OxPhos inhibition downregulates multiple pathways required for CSC function, 
      such as the mevalonate pathway, YAP, Myc, and the HIF pathway. ClpP agonists 
      showed significantly greater inhibitory effect on CSC functions compared with 
      other mitochondria-targeting drugs. Further studies showed that ClpP agonists 
      deplete NAD(P)+ and NAD(P)H, induce redox imbalance, dysregulate one-carbon 
      metabolism and proline biosynthesis. Downregulation of these pathways by ClpP 
      agonists further contribute to the inhibition of CSC function. In conclusion, 
      ClpP agonists inhibit breast CSC functions by disrupting mitochondrial 
      homeostasis in breast cancer cells and inhibiting multiple pathways critical to 
      CSC function. SIGNIFICANCE: ClpP agonists disrupt mitochondrial homeostasis by 
      activating mitochondrial matrix protease ClpP. We report that ClpP agonists 
      inhibit cell growth and cancer stem cell functions in breast cancer models by 
      modulating multiple metabolic pathways essential to cancer stem cell function.
FAU - Greer, Yoshimi Endo
AU  - Greer YE
AD  - Women's Malignancies Branch, NCI, NIH, Bethesda, MD.
FAU - Hernandez, Lidia
AU  - Hernandez L
AD  - Women's Malignancies Branch, NCI, NIH, Bethesda, MD.
FAU - Fennell, Emily M J
AU  - Fennell EMJ
AD  - Department of Pharmacology, University of North Carolina School of Medicine, 
      Chapel Hill, NC.
FAU - Kundu, Manjari
AU  - Kundu M
AD  - Women's Malignancies Branch, NCI, NIH, Bethesda, MD.
FAU - Voeller, Donna
AU  - Voeller D
AD  - Women's Malignancies Branch, NCI, NIH, Bethesda, MD.
FAU - Chari, Raj
AU  - Chari R
AD  - Genome Modification Core, Frederick National Laboratory for Cancer Research, NCI, 
      NIH, Frederick, MD.
FAU - Gilbert, Samuel F
AU  - Gilbert SF
AD  - Women's Malignancies Branch, NCI, NIH, Bethesda, MD.
FAU - Gilbert, Thomas S K
AU  - Gilbert TSK
AD  - Department of Pharmacology, University of North Carolina School of Medicine, 
      Chapel Hill, NC.
FAU - Ratnayake, Shashikala
AU  - Ratnayake S
AD  - Center for Biomedical Informatics and Information Technology, National Cancer 
      Institute, Rockville, MD.
FAU - Tang, Binwu
AU  - Tang B
AD  - Laboratory of Cancer Biology and Genetics, NCI, NIH.
FAU - Hafner, Markus
AU  - Hafner M
AD  - RNA Molecular Biology Group, Laboratory of Muscle Stem Cells and Gene Regulation, 
      NIAMS, NIH, Bethesda, MD.
FAU - Chen, Qingrong
AU  - Chen Q
AD  - Center for Biomedical Informatics and Information Technology, National Cancer 
      Institute, Rockville, MD.
FAU - Meerzaman, Daoud
AU  - Meerzaman D
AD  - Center for Biomedical Informatics and Information Technology, National Cancer 
      Institute, Rockville, MD.
FAU - Iwanowicz, Edwin
AU  - Iwanowicz E
AD  - Madera Therapeutics, LLC, Cary, NC.
FAU - Annunziata, Christina M
AU  - Annunziata CM
AD  - Women's Malignancies Branch, NCI, NIH, Bethesda, MD.
FAU - Graves, Lee M
AU  - Graves LM
AD  - Department of Pharmacology, University of North Carolina School of Medicine, 
      Chapel Hill, NC.
FAU - Lipkowitz, Stanley
AU  - Lipkowitz S
AD  - Women's Malignancies Branch, NCI, NIH, Bethesda, MD.
LA  - eng
GR  - R01 GM138520/GM/NIGMS NIH HHS/United States
GR  - ZIA SC007263/ImNIH/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
PL  - United States
TA  - Cancer Res Commun
JT  - Cancer research communications
JID - 9918281580506676
RN  - EC 3.4.- (Peptide Hydrolases)
RN  - 0U46U6E8UK (NAD)
RN  - EC 3.4.- (Endopeptidases)
RN  - EC 3.4.21.92 (ClpP protein, human)
RN  - EC 3.4.21.92 (Endopeptidase Clp)
MH  - Humans
MH  - Female
MH  - *Breast Neoplasms/drug therapy
MH  - Peptide Hydrolases/metabolism
MH  - NAD/metabolism
MH  - Neoplasm Recurrence, Local/metabolism
MH  - Mitochondria
MH  - Homeostasis
MH  - Endopeptidases/metabolism
MH  - Neoplastic Stem Cells
MH  - Endopeptidase Clp/metabolism
PMC - PMC9645232
MID - NIHMS1836599
COIS- Conflict of interest disclosure EJI has a financial interest in Madera 
      Therapeutics. The other authors declare no potential conflicts of interest.
EDAT- 2022/11/18 06:00
MHDA- 2022/11/18 06:01
PMCR- 2022/10/10
CRDT- 2022/11/17 12:13
PHST- 2022/11/17 12:13 [entrez]
PHST- 2022/11/18 06:00 [pubmed]
PHST- 2022/11/18 06:01 [medline]
PHST- 2022/10/10 00:00 [pmc-release]
AID - CRC-22-0142 [pii]
AID - 10.1158/2767-9764.CRC-22-0142 [doi]
PST - ppublish
SO  - Cancer Res Commun. 2022 Oct 10;2(10):1144-1161. doi: 
      10.1158/2767-9764.CRC-22-0142.