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The combination of lactoferrin and linolenic acid inhibits colorectal tumor growth through activating AMPK/JNK-related apoptosis pathway.

ABSTRACT: Colorectal cancer is a common cause of death with few available therapeutic strategies, and the preventative complexes in adjunctive therapy are urgently needed. Increasing evidences have shown that natural ingredients, including lactoferrin, oleic acid, docosahexaenoic acid (DHA) and linolenic acid, possess anti-inflammatory and anti-tumor activities. However, investigations and comparisons of their combinations in colorectal tumor model have not been reported, and the mechanism is still unrevealed. In the study, we examined the viability, migration, invasion and apoptosis of HT29 cells to choose the proper doses of these components and to select the effective combination in vitro. BALB/c nude mice bearing colorectal tumor were used to explore the role of selected combination in inhibiting tumor development in vivo. Additionally, metabonomic detection was performed to screen out the specific changed metabolitesand related pathway. The results demonstrated that lactoferrin at 6.25 μM, oleic acid at 0.18 mM, DHA at 0.18 mM, and linolenic acid at 0.15 mM significantly inhibited the viabilities of HT29 cells (p < 0.05). The combination of lactoferrin (6.25 μM) + linolenic acid (0.15 mM) exhibited the strongest activity in inhibiting the migration and invasion of HT29 cells in vivo and suppressing tumor development in vitro (p < 0.05). Furthermore, the lactoferrin + linolenic acid combination activated p-AMPK and p-JNK, thereby inducing apoptosis of HT29 cells (p < 0.05). The present study was the first to show that lactoferrin + linolenic acid combination inhibited HT29 tumor formation by activating AMPK/JNK related pathway.

SUBMITTER: Yao Q

PROVIDER: S-EPMC8174148 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:AMP-activated Protein Kinase (AMPK) is a stress-activated kinase that protects against cardiomyocyte injury during ischemia and reperfusion. c-Jun N-terminal kinase (JNK), a mitogen activated protein kinase, is activated by ischemia and reperfusion. NF-?B is an important transcription factor involved in ischemia and reperfusion injury. METHODS AND RESULTS:The intrinsic activation of AMPK attenuates the inflammation which occurred during ischemia/reperfusion through the modulation of the JNK mediated NF-?B signaling pathway. Rat cardiac myoblast H9c2 cells were subjected to hypoxia and/or reoxygenation to investigate the signal transduction that occurred during myocardial ischemia/reperfusion. Mitochondrial function was measured by the Seahorse XF24 V7 PS system. Hypoxia treatment triggered AMPK activation in H9c2 cells in a time dependent manner. The inhibition of hypoxic AMPK activation through a pharmacological approach (Compound C) or siRNA knockdown of AMPK ? catalytic subunits caused dramatic augmentation in JNK activation, inflammatory NF-?B phosphorylation, and apoptosis during hypoxia and reoxygenation. Inhibition of AMPK activation significantly impaired mitochondrial function and increased the generation of reactive oxygen species (ROS) during hypoxia and reoxygenation. In contrast, pharmacological activation of AMPK by metformin significantly inhibited mitochondrial permeability transition pore (mPTP) opening and ROS generation. Moreover, AMPK activation significantly attenuated the JNK-NF-?B signaling cascade and inhibited mRNA and protein levels of pro-inflammatory cytokines, such as TNF-? and IL-6, during hyopoxia/reoxygenation in H9c2 cells. Intriguingly, both pharmacologic inhibition of JNK by JNK-IN-8 and siRNA knockdown of JNK signaling pathway attenuated NF-?B phosphorylation and apoptosis but did not affect AMPK activation in response to hypoxia and reoxygenation. CONCLUSIONS:AMPK activation modulates JNK-NF-?B signaling cascade during hypoxia and reoxygenation stress conditions. Cardiac AMPK activation plays a critical role in maintaining mitochondrial function and inhibiting the inflammatory response caused by ischemic insults.

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The combination of lactoferrin and linolenic acid inhibits colorectal tumor growth through activating AMPK/JNK-related apoptosis pathway.

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