TY - JOUR
T1 - Momordicine-I suppresses head and neck cancer growth by modulating key metabolic pathways
AU - Bandyopadhyay, Debojyoty
AU - Tran, Ellen T.
AU - Patel, Ruchi A.
AU - Luetzen, Matthew A.
AU - Cho, Kevin
AU - Shriver, Leah P.
AU - Patti, Gary J.
AU - Varvares, Mark A.
AU - Ford, David A.
AU - McCommis, Kyle S.
AU - Ray, Ratna B.
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
N2 - One of the hallmarks of cancer is metabolic reprogramming which controls cellular homeostasis and therapy resistance. Here, we investigated the effect of momordicine-I (M-I), a key bioactive compound from Momordica charantia (bitter melon), on metabolic pathways in human head and neck cancer (HNC) cells and a mouse HNC tumorigenicity model. We found that M-I treatment on HNC cells significantly reduced the expression of key glycolytic molecules, SLC2A1 (GLUT-1), HK1, PFKP, PDK3, PKM, and LDHA at the mRNA and protein levels. We further observed reduced lactate accumulation, suggesting glycolysis was perturbed in M-I treated HNC cells. Metabolomic analyses confirmed a marked reduction in glycolytic and TCA cycle metabolites in M-I-treated cells. M-I treatment significantly downregulated mRNA and protein expression of essential enzymes involved in de novo lipogenesis, including ACLY, ACC1, FASN, SREBP1, and SCD1. Using shotgun lipidomics, we found a significant increase in lysophosphatidylcholine and phosphatidylcholine loss in M-I treated cells. Subsequently, we observed dysregulation of mitochondrial membrane potential and significant reduction of mitochondrial oxygen consumption after M-I treatment. We further observed M-I treatment induced autophagy, activated AMPK and inhibited mTOR and Akt signaling pathways and leading to apoptosis. However, blocking autophagy did not rescue the M-I-mediated alterations in lipogenesis, suggesting an independent mechanism of action. M-I treated mouse HNC MOC2 cell tumors displayed reduced Hk1, Pdk3, Fasn, and Acly expression. In conclusion, our study revealed that M-I inhibits glycolysis, lipid metabolism, induces autophagy in HNC cells and reduces tumor volume in mice. Therefore, M-I-mediated metabolic reprogramming of HNC has the potential for important therapeutic implications.
AB - One of the hallmarks of cancer is metabolic reprogramming which controls cellular homeostasis and therapy resistance. Here, we investigated the effect of momordicine-I (M-I), a key bioactive compound from Momordica charantia (bitter melon), on metabolic pathways in human head and neck cancer (HNC) cells and a mouse HNC tumorigenicity model. We found that M-I treatment on HNC cells significantly reduced the expression of key glycolytic molecules, SLC2A1 (GLUT-1), HK1, PFKP, PDK3, PKM, and LDHA at the mRNA and protein levels. We further observed reduced lactate accumulation, suggesting glycolysis was perturbed in M-I treated HNC cells. Metabolomic analyses confirmed a marked reduction in glycolytic and TCA cycle metabolites in M-I-treated cells. M-I treatment significantly downregulated mRNA and protein expression of essential enzymes involved in de novo lipogenesis, including ACLY, ACC1, FASN, SREBP1, and SCD1. Using shotgun lipidomics, we found a significant increase in lysophosphatidylcholine and phosphatidylcholine loss in M-I treated cells. Subsequently, we observed dysregulation of mitochondrial membrane potential and significant reduction of mitochondrial oxygen consumption after M-I treatment. We further observed M-I treatment induced autophagy, activated AMPK and inhibited mTOR and Akt signaling pathways and leading to apoptosis. However, blocking autophagy did not rescue the M-I-mediated alterations in lipogenesis, suggesting an independent mechanism of action. M-I treated mouse HNC MOC2 cell tumors displayed reduced Hk1, Pdk3, Fasn, and Acly expression. In conclusion, our study revealed that M-I inhibits glycolysis, lipid metabolism, induces autophagy in HNC cells and reduces tumor volume in mice. Therefore, M-I-mediated metabolic reprogramming of HNC has the potential for important therapeutic implications.
KW - Autophagy
KW - Glycolysis
KW - Head and neck cancer
KW - Lipid metabolism
KW - Metabolites
KW - Momordicine-I
UR - http://www.scopus.com/inward/record.url?scp=85212437895&partnerID=8YFLogxK
U2 - 10.1186/s12964-024-01951-w
DO - 10.1186/s12964-024-01951-w
M3 - Article
C2 - 39696286
AN - SCOPUS:85212437895
SN - 1478-811X
VL - 22
JO - Cell Communication and Signaling
JF - Cell Communication and Signaling
IS - 1
M1 - 597
ER -