Lupeol suppresses plasminogen activator inhibitor-1-mediated macrophage recruitment and attenuates M2 macrophage
Hyun-Ji Park1, Gyoo-Yong Chi1, Yung-Hyun Choi2
1Department of Pathology, College of Korean Medicine, Dong-eui University, Busan, 47227, Republic of Korea.
Abstract:
Tumor-associated macrophages (TAMs) are closely related with poor prognosis of cancers. The current study investigated whether lupeol regulates TAMs by focusing on the recruitment and polarization of macrophages. We found that lupeol suppressed the recruitment of THP-1 macrophages (THP-1 cells differentiated into macrophages) towards H1299 lung carcinoma cells by inhibiting plasminogen activator inhibitor-1 (PAI-1) production from H1299 cells. The reduced migration of THP-1 macrophages by lupeol was recovered by adding recombinant human PAI-1 as a chemoattractant. Knockdown of PAI-1 or treatment of tiplaxtinin, a PAI-1 inhibitor, in H1299 cells abrogated the chemotaxis of macrophages. Furthermore, lupeol suppressed the interleukin (IL)-4- and IL-13-induced M2 macrophage polarization. The mRNA expression of M2 macrophage markers and the phosphorylation of signal transducer and activator of transcription 6 (STAT6) were commonly decreased by lupeol in RAW264.7 cells. In addition, lupeol-suppressed M2 macrophage polarization led to the reduced migration of Lewis lung carcinoma (LLC) cells. Taken together, our results suggest that lupeol attenuates PAI-1-mediated macrophage recruitment towards cancer cells and inhibits M2 macrophage polarization.
Insights
Lupeol inhibits cancer cell recruitment of macrophages by reducing plasminogen activator inhibitor-1 (PAI-1) and suppresses M2 macrophage polarization, offering a potential therapeutic strategy for cancer. This impacts tumor progression and patient prognosis.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Tumor-associated macrophages (TAMs) are crucial in cancer progression and are linked to poor patient prognosis.
- Understanding the regulatory mechanisms of TAM recruitment and polarization is vital for developing novel cancer therapies.
Purpose of the Study:
- To investigate the role of lupeol in regulating TAMs, specifically focusing on macrophage recruitment and polarization.
- To elucidate the molecular mechanisms by which lupeol affects macrophage behavior in the tumor microenvironment.
Main Methods:
- Assessing lupeol's effect on THP-1 macrophage recruitment towards H1299 lung carcinoma cells.
- Investigating the role of plasminogen activator inhibitor-1 (PAI-1) in lupeol-mediated macrophage migration inhibition.
- Analyzing lupeol's impact on interleukin (IL)-4 and IL-13-induced M2 macrophage polarization in RAW264.7 cells.
- Evaluating the effect of lupeol-modulated M2 polarization on Lewis lung carcinoma (LLC) cell migration.
Main Results:
- Lupeol suppressed THP-1 macrophage recruitment to H1299 cells by inhibiting PAI-1 production.
- Recombinant PAI-1 restored lupeol-impaired macrophage migration, confirming PAI-1's chemoattractant role.
- PAI-1 knockdown or inhibition abrogated macrophage chemotaxis towards cancer cells.
- Lupeol inhibited M2 macrophage polarization, decreasing M2 marker expression and STAT6 phosphorylation.
- Suppression of M2 polarization by lupeol reduced Lewis lung carcinoma cell migration.
Conclusions:
- Lupeol attenuates PAI-1-mediated macrophage recruitment to cancer cells.
- Lupeol effectively inhibits M2 macrophage polarization, a key process in tumor progression.
- These findings suggest lupeol as a potential therapeutic agent targeting TAMs in cancer treatment.
