Related Experiment Video

Updated: May 30, 2025

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
08:45

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors

Published on: July 17, 2020

6.2K

Dual targeting PPARα and NPC1L1 metabolic vulnerabilities blocks tumorigenesis

Xiaona You1, Xi Hu2, Zenghui Sun2

  • 1Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China; School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.

Cancer Letters
|January 25, 2025
PubMed

Insights

Targeting lipid metabolism in breast cancer, this study found that inhibiting Niemann-Pick C1-like 1 (NPC1L1) alongside activating peroxisome proliferator-activated receptor α (PPARα) induced cancer cell death and suppressed tumor growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Metabolic Pathways

Background:

  • Dysregulated lipid metabolism is a hallmark of cancer, influencing tumor progression.
  • PKM2 (Pyruvate Kinase M2) plays a role in cancer metabolism, but its downstream effectors are not fully understood.
  • Niemann-Pick C1-like 1 (NPC1L1) is involved in cholesterol absorption and its role in cancer is emerging.

Purpose of the Study:

  • To investigate the role of NPC1L1 as a downstream target of PKM2 in breast cancer.
  • To explore the therapeutic potential of targeting NPC1L1 and PPARα signaling in breast cancer.

Main Methods:

  • Utilized PKM2 knockout (KO) breast cancer cell models.
  • Investigated the effects of fenofibrate (PPARα activator) and ezetimibe (NPC1L1 inhibitor) on cell apoptosis and tumor growth.
  • Analyzed molecular mechanisms including transcription factor recruitment, IRE1α/XBP1s pathway activation, and histone modifications (H3K27 demethylation).

Main Results:

  • PKM2 KO enhanced NPC1L1 expression and downregulated PPARα signaling.
  • Fenofibrate and ezetimibe synergistically induced breast cancer cell apoptosis via IRE1α/XBP1s/KDM6B pathway activation and H3K27 acetylation.
  • Combined treatment significantly inhibited tumor growth in vivo.

Conclusions:

  • NPC1L1 is a downstream effector of PKM2 in breast cancer.
  • Dual targeting of PPARα and NPC1L1 presents a promising novel therapeutic strategy for breast cancer.
  • The IRE1α/XBP1s/KDM6B axis mediates the anti-cancer effects of combined fenofibrate and ezetimibe treatment.
Keywords:
Lipid metabolismNPC1L1PKM2PPARαSynergistic effect

More Related Videos

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer06:51

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer

Published on: July 21, 2018

17.7K
Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists10:51

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists

Published on: November 15, 2013

12.7K

Related Concept Videos

Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.4K
Transducer Mechanism: Nuclear Receptors01:31

Transducer Mechanism: Nuclear Receptors

Nuclear receptors, or NRs, are unique transcription factors that regulate gene transcription and affect the cellular pathways involved in reproduction, development, or metabolism. Their ability to be stimulated by small lipophilic ligands and control vital cellular processes makes them ideal drug targets. Nearly 10-15% of currently prescribed drugs target these receptors.
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
1.3K
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
7.4K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.7K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
3.4K
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
6.2K