Let-7g Upregulation Attenuated the KRAS-PI3K-Rac1-Akt Axis-Mediated Bioenergetic Functions

Kuang-Chen Hung; Ni Tien; Da-Tian Bau; Chun-Hsu Yao; Chan-Hung Chen; Jiun-Long Yang; Meng-Liang Lin; Shih-Shun Chen

doi:10.3390/cells12182313

Let-7g Upregulation Attenuated the KRAS-PI3K-Rac1-Akt Axis-Mediated Bioenergetic Functions

Cells. 2023 Sep 19;12(18):2313. doi: 10.3390/cells12182313.

Authors

Kuang-Chen Hung^{1

2

3}, Ni Tien⁴, Da-Tian Bau⁵, Chun-Hsu Yao⁶, Chan-Hung Chen⁷, Jiun-Long Yang⁸, Meng-Liang Lin⁷, Shih-Shun Chen⁹

Affiliations

¹ Division of Neurosurgery, Department of Surgery, Taichung Army Force General Hospital, Taichung 41152, Taiwan.
² Department of Surgery, National Defense Medical Center, Taipei 11490, Taiwan.
³ General Education Center, College of Humanities and General Education, Central Taiwan University of Science and Technology, Taichung 406053, Taiwan.
⁴ Department of Laboratory Medicine, China Medical University Hospital, Taichung 404394, Taiwan.
⁵ Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404333, Taiwan.
⁶ Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung 404333, Taiwan.
⁷ Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404333, Taiwan.
⁸ Department of Nursing, St. Mary's Junior College of Medicine, Nursing and Management, Yilan 26644, Taiwan.
⁹ Department of Medical Laboratory Science and Biotechnology, College of Medical and Health Science, Asia University, Taichung 413305, Taiwan.

Abstract

The aberrant activation of signaling pathways contributes to cancer cells with metabolic reprogramming. Thus, targeting signaling modulators is considered a potential therapeutic strategy for cancer. Subcellular fractionation, coimmunoprecipitation, biochemical analysis, and gene manipulation experiments revealed that decreasing the interaction of kirsten rat sarcoma viral oncogene homolog (KRAS) with p110α in lipid rafts with the use of naringenin (NGN), a citrus flavonoid, causes lipid raft-associated phosphatidylinositol 3-kinase (PI3K)-GTP-ras-related C3 botulinum toxin substrate 1 (Rac1)-protein kinase B (Akt)-regulated metabolic dysfunction of glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), leading to apoptosis in human nasopharyngeal carcinoma (NPC) cells. The use of lethal-7g (let-7g) mimic and let-7g inhibitor confirmed that elevated let-7g resulted in a decrease in KRAS expression, which attenuated the PI3K-Rac1-Akt-BCL-2/BCL-x_L-modulated mitochondrial energy metabolic functions. Increased let-7g depends on the suppression of the RNA-specificity of monocyte chemoattractant protein-induced protein-1 (MCPIP1) ribonuclease since NGN specifically blocks the degradation of pre-let-7g by NPC cell-derived immunoprecipitated MCPIP1. Converging lines of evidence indicate that the inhibition of MCPIP1 by NGN leads to let-7g upregulation, suppressing oncogenic KRAS-modulated PI3K-Rac1-Akt signaling and thereby impeding the metabolic activities of aerobic glycolysis and mitochondrial OXPHOS.

Keywords: KRAS; MCPIP1; bioenergetic metabolism; let-7g; naringenin.

Grants and funding

K.-C.H. was supported by grant from the Armed Force Taichung General Hospital (TCAFGH-D-109020). S.-S.C. was supported by grants from the Armed Force Taichung General Hospital (TCAFGH-D-109020) and Central Taiwan University of Science and Technology (CTU109-P-101), Taiwan. M.-L.L. was supported by grants from the China Medical University (CMU109-S-32 and CMU110-S33) and the Ministry of Science and Technology (MOST 107-2635-B-039-001), Taiwan.