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Published on: October 21, 2022
SLC44A2 negatively regulates mitochondrial fatty acid oxidation to suppress colorectal progression by blocking the
Ying Yang1, Longlong Zheng1, Jiaxing He1
1Department of General Surgery, Tangdu Hospital, the Air Force Medical University, Xi'an, 710038, China.
Abstract:
The dependence of cancer cells on mitochondrial metabolism has been revealed in various cancer types. However, the mechanisms underlying this metabolic remodeling remain largely unclear. Solute carrier family 44 member 4 (SLC44A2) is a mitochondrial membrane-localized transmembrane protein belonging to the choline transporter-like protein family. Recently, it was reported that deletion of SLC44A2 impairs adhesion and increases proliferation in cultured lung mesenchymal cells. This finding implies that SLC44A2 may play a role in the malignant phenotypes of human cancers. However, the effects of SLC44A2 on malignant phenotypes and mitochondrial metabolism in human cancers remain unexplored. In the present investigation, we observed a significant reduction in SLC44A2 expression in colorectal cancer (CRC), and low SLC44A2 expression was closely associated with poorer survival of CRC patients. Functional assays demonstrated that SLC44A2 suppressed CRC growth and metastasis both in vitro and in vivo. Mechanistically, SLC44A2 inhibits mitochondrial fatty acid oxidation, thereby reducing energy supply and increase ROS stress. This effect is achieved by promoting mitochondrial E3 ubiquitin ligase 1 (MUL1)-regulated degradation of carnitine palmitoyltransferase 2 (CPT2) via enhancing the interaction between MUL1 and CPT2, without increasing MUL1 expression, which ultimately contributes to the proliferation and metastasis of CRC. Together, SLC44A2 functions as a critical tumor suppressor in CRC and potential therapeutic target in the treatment of this malignancy.
Insights
Solute carrier family 44 member 4 (SLC44A2) acts as a tumor suppressor in colorectal cancer (CRC). Reduced SLC44A2 expression promotes CRC growth and metastasis by altering mitochondrial metabolism.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Cancer cells exhibit increased reliance on mitochondrial metabolism, yet the underlying mechanisms are not fully understood.
- Solute carrier family 44 member 4 (SLC44A2), a mitochondrial protein, has been implicated in cell adhesion and proliferation, suggesting a potential role in cancer.
- The specific function of SLC44A2 in human cancer malignancy and mitochondrial metabolism remains largely unexplored.
Purpose of the Study:
- To investigate the role of SLC44A2 in colorectal cancer (CRC) progression and its impact on mitochondrial metabolism.
- To elucidate the molecular mechanisms by which SLC44A2 influences CRC cell growth and metastasis.
Main Methods:
- Analysis of SLC44A2 expression levels in CRC tissues and correlation with patient survival.
- In vitro and in vivo functional assays to assess the effects of SLC44A2 on CRC growth and metastasis.
- Mechanistic studies involving mitochondrial fatty acid oxidation, reactive oxygen species (ROS) stress, and protein-protein interactions (SLC44A2, MUL1, CPT2).
Main Results:
- SLC44A2 expression is significantly reduced in CRC, and lower levels correlate with poorer patient survival.
- SLC44A2 suppresses CRC growth and metastasis both in vitro and in vivo.
- SLC44A2 inhibits mitochondrial fatty acid oxidation by promoting MUL1-mediated degradation of CPT2, leading to reduced energy supply and increased ROS stress.
Conclusions:
- SLC44A2 functions as a critical tumor suppressor in colorectal cancer.
- SLC44A2's regulation of mitochondrial metabolism is a key mechanism underlying its tumor-suppressive role.
- SLC44A2 represents a potential therapeutic target for colorectal cancer treatment.
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