PMID- 36251722
OWN - NLM
STAT- MEDLINE
DCOM- 20230105
LR  - 20230705
IS  - 1940-6215 (Electronic)
IS  - 1940-6207 (Print)
IS  - 1940-6215 (Linking)
VI  - 16
IP  - 1
DP  - 2023 Jan 4
TI  - Withaferin A Inhibits Fatty Acid Synthesis in Rat Mammary Tumors.
PG  - 5-16
LID - 10.1158/1940-6207.CAPR-22-0193 [doi]
AB  - Withaferin A (WA), which is a small molecule derived from a medicinal plant 
      (Withania somnifera), inhibits growth of human breast cancer xenografts and 
      mammary tumor development in rodent models without any toxicity. However, the 
      mechanism underlying inhibition of mammary cancer development by WA 
      administration is not fully understood. Herein, we demonstrate that the fatty 
      acid synthesis pathway is a novel target of WA in mammary tumors. Treatment of 
      MCF-7 and MDA-MB-231 cells with WA resulted in suppression of fatty acid 
      metabolizing enzymes, including ATP-citrate lyase (ACLY), acetyl-CoA carboxylase 
      1 (ACC1), fatty acid synthase (FASN), and carnitine palmitoyltransferase 1A 
      (CPT1A). Expression of FASN and CPT1A was significantly higher in 
      N-methyl-N-nitrosourea-induced mammary tumors in rats when compared with normal 
      mammary tissues. WA-mediated inhibition of mammary tumor development in rats was 
      associated with a statistically significant decrease in expression of ACC1 and 
      FASN and suppression of plasma and/or mammary tumor levels of total free fatty 
      acids and phospholipids. WA administration also resulted in a significant 
      increase in percentage of natural killer cells in the spleen. The protein level 
      of sterol regulatory element binding protein 1 (SREBP1) was decreased in 
      MDA-MB-231 cells after WA treatment. Overexpression of SREBP1 in MDA-MB-231 cells 
      conferred partial but significant protection against WA-mediated downregulation 
      of ACLY and ACC1. In conclusion, circulating and/or mammary tumor levels of fatty 
      acid synthesis enzymes and total free fatty acids may serve as biomarkers of WA 
      efficacy in future clinical trials. PREVENTION RELEVANCE: The present study shows 
      that breast cancer prevention by WA in rats is associated with suppression of 
      fatty acid synthesis.
CI  - (c)2022 American Association for Cancer Research.
FAU - Singh, Krishna B
AU  - Singh KB
AUID- ORCID: 0000-0002-4052-4373
AD  - Department of Pharmacology and Chemical Biology, University of Pittsburgh, 
      Pittsburgh, Pennsylvania.
FAU - Hahm, Eun-Ryeong
AU  - Hahm ER
AUID- ORCID: 0000-0002-3197-4575
AD  - Department of Pharmacology and Chemical Biology, University of Pittsburgh, 
      Pittsburgh, Pennsylvania.
FAU - Kim, Su-Hyeong
AU  - Kim SH
AUID- ORCID: 0000-0003-2071-613X
AD  - Department of Pharmacology and Chemical Biology, University of Pittsburgh, 
      Pittsburgh, Pennsylvania.
FAU - Singh, Shivendra V
AU  - Singh SV
AUID- ORCID: 0000-0002-3733-144X
AD  - Department of Pharmacology and Chemical Biology, University of Pittsburgh, 
      Pittsburgh, Pennsylvania.
AD  - UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania.
LA  - eng
GR  - R01 CA142604/CA/NCI NIH HHS/United States
GR  - R01 CA219180/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Cancer Prev Res (Phila)
JT  - Cancer prevention research (Philadelphia, Pa.)
JID - 101479409
RN  - L6DO3QW4K5 (withaferin A)
RN  - 0 (Fatty Acids, Nonesterified)
RN  - 0 (Withanolides)
RN  - 0 (Fatty Acids)
SB  - IM
MH  - Rats
MH  - Humans
MH  - Animals
MH  - Female
MH  - Fatty Acids, Nonesterified/therapeutic use
MH  - Apoptosis
MH  - *Withanolides/pharmacology/therapeutic use
MH  - *Breast Neoplasms/pathology
MH  - *Mammary Neoplasms, Animal/drug therapy
MH  - Fatty Acids
PMC - PMC9812931
MID - NIHMS1844594
COIS- Conflict of Interest: The authors declare no potential conflict of interest.
EDAT- 2022/10/18 06:00
MHDA- 2023/01/06 06:00
PMCR- 2023/07/04
CRDT- 2022/10/17 13:44
PHST- 2022/04/28 00:00 [received]
PHST- 2022/07/29 00:00 [revised]
PHST- 2022/10/13 00:00 [accepted]
PHST- 2022/10/18 06:00 [pubmed]
PHST- 2023/01/06 06:00 [medline]
PHST- 2022/10/17 13:44 [entrez]
PHST- 2023/07/04 00:00 [pmc-release]
AID - 709785 [pii]
AID - 10.1158/1940-6207.CAPR-22-0193 [doi]
PST - ppublish
SO  - Cancer Prev Res (Phila). 2023 Jan 4;16(1):5-16. doi: 
      10.1158/1940-6207.CAPR-22-0193.