PMID- 38066600
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20231209
IS  - 2049-3002 (Print)
IS  - 2049-3002 (Electronic)
IS  - 2049-3002 (Linking)
VI  - 11
IP  - 1
DP  - 2023 Dec 8
TI  - A HIF-1alpha inhibitor combined with palmitic acid and L-carnitine treatment can 
      prevent the fat metabolic reprogramming under hypoxia and induce apoptosis in 
      hepatocellular carcinoma cells.
PG  - 25
LID - 10.1186/s40170-023-00328-w [doi]
LID - 25
AB  - BACKGROUND: A hypoxic environment often persists within solid tumors, including 
      hepatocellular carcinoma (HCC). Hypoxia-inducible factor-1alpha (HIF-1alpha) can 
      accelerate cancer malignancy by inducing hypoxia-dependent expression of various 
      genes. Tumor hypoxia can also induce metabolic reprogramming of fatty acid (FA) 
      metabolism, through which HIF-1alpha plays an essential role in diminishing fatty 
      acid beta-oxidation (FAO) in hypoxic cancer cells. METHODS: We aimed to investigate 
      potential new drug therapy options for targeting hypoxic cancer cells within HCC 
      tumors, specifically through combining HIF-1alpha inhibition with palmitic acid 
      (PA) + L-carnitine (LC) treatment to effectively induce apoptosis in hypoxic HCC 
      cells. To test this hypothesis, in vitro and in vivo studies were performed. 
      RESULTS: We first demonstrated that hypoxia-dependent apoptosis was induced by an 
      overload of PA in two HCC cell lines (HepG2 and Hep3B) via excessive production 
      of reactive oxygen species (ROS). Moreover, this observed PA-induced apoptosis 
      was enhanced by HIF-1alpha knockdown (KD) in these cells under hypoxia. In addition, 
      the combination of PA with FAO activator LC increased FAO activity and led to 
      stronger cell death than PA alone in hypoxic HIF-1alpha KD cells, specifically 
      through further ROS generation. To clarify the mechanism of hypoxia-induced FA 
      metabolism reprogramming, expression levels of the genes encoding FAO enzymes 
      CPT1A, ACSL1, MCAD, and LCAD, FA transporter CD36, and FA esterification enzymes 
      DGAT and APGAT were analyzed using HIF-1alpha KD and scramble control (SC) cells. The 
      results suggested that HIF-1alpha could repress mRNA expression of the FAO-related 
      enzymes and CD36, while it upregulated FA esterification gene expression. This 
      suggested a central role for HIF-1alpha in hypoxia-induced reprogramming of FA 
      metabolism in HCC cells. Using a nude mouse model, PA administration was found to 
      induce apoptosis from ROS overproduction in HIF-1alpha KD tumors compared with SC 
      tumors. Additional LC treatment synergistically enhanced the PA-induced apoptosis 
      in HIF-1alpha KD tumors. Finally, in vivo therapy composed of HIF-1alpha inhibitor YC-1 
      with PA + LC could induce ROS-mediated apoptosis in HepG2 tumors without 
      significant toxicity. CONCLUSIONS: A combination therapy of YC-1 with PA + LC may 
      be a unique anti-tumor therapy for targeting hypoxic HCC cells, specifically by 
      ROS overproduction leading to forced FAO activation.
CI  - (c) 2023. The Author(s).
FAU - Matsufuji, Shohei
AU  - Matsufuji S
AD  - Department of Surgery, Saga University Faculty of Medicine, Saga, 849-8501, 
      Japan.
FAU - Kitajima, Yoshihiko
AU  - Kitajima Y
AD  - Department of Surgery, National Hospital Organization, Higashisaga Hospital, 
      Saga, Miyaki, 849-0101, Japan. n.island1102@gmail.com.
FAU - Higure, Kazuki
AU  - Higure K
AD  - Department of Surgery, Saga University Faculty of Medicine, Saga, 849-8501, 
      Japan.
FAU - Kimura, Naoya
AU  - Kimura N
AD  - Department of Surgery, Saga University Faculty of Medicine, Saga, 849-8501, 
      Japan.
FAU - Maeda, Sachiko
AU  - Maeda S
AD  - Department of Pathology, Saga University Faculty of Medicine, Saga, 849-8501, 
      Japan.
FAU - Yamada, Kohei
AU  - Yamada K
AD  - Department of Surgery, Saga University Faculty of Medicine, Saga, 849-8501, 
      Japan.
FAU - Ito, Kotaro
AU  - Ito K
AD  - Department of Surgery, Saga University Faculty of Medicine, Saga, 849-8501, 
      Japan.
FAU - Tanaka, Tomokazu
AU  - Tanaka T
AD  - Department of Surgery, Saga University Faculty of Medicine, Saga, 849-8501, 
      Japan.
FAU - Kai, Keita
AU  - Kai K
AD  - Department of Pathology, Saga University Faculty of Medicine, Saga, 849-8501, 
      Japan.
FAU - Noshiro, Hirokazu
AU  - Noshiro H
AD  - Department of Surgery, Saga University Faculty of Medicine, Saga, 849-8501, 
      Japan.
LA  - eng
PT  - Journal Article
DEP - 20231208
PL  - England
TA  - Cancer Metab
JT  - Cancer & metabolism
JID - 101607582
PMC - PMC10709876
OTO - NOTNLM
OT  - Fatty acid oxidation
OT  - HCC
OT  - HIF-1alpha
OT  - Hypoxia
OT  - L-carnitine
OT  - Palmitic acids
OT  - ROS
OT  - YC-1
COIS- The authors declare no competing interests.
EDAT- 2023/12/09 10:44
MHDA- 2023/12/09 10:45
PMCR- 2023/12/08
CRDT- 2023/12/09 00:12
PHST- 2023/08/23 00:00 [received]
PHST- 2023/11/29 00:00 [accepted]
PHST- 2023/12/09 10:45 [medline]
PHST- 2023/12/09 10:44 [pubmed]
PHST- 2023/12/09 00:12 [entrez]
PHST- 2023/12/08 00:00 [pmc-release]
AID - 10.1186/s40170-023-00328-w [pii]
AID - 328 [pii]
AID - 10.1186/s40170-023-00328-w [doi]
PST - epublish
SO  - Cancer Metab. 2023 Dec 8;11(1):25. doi: 10.1186/s40170-023-00328-w.