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Curcumin Suppresses M2 Macrophage-derived Paclitaxel Chemoresistance through Inhibition of PI3K-AKT/STAT3 Signaling
Bhawna Deswal1,2, Urmi Bagchi1, Sonia Kapoor1
1Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida, Uttar Pradesh, 201313, India.
Background:
Breast cancer is the leading cancer in women worldwide. The development of chemoresistance that leads to recurrence and mortality remains a major concern. M2-type tumor-associated macrophages (TAMs), present in the breast tumor microenvironment, secrete various cytokines and growth factors that induce chemoresistance. Curcumin, isolated from Curcuma longa, is known to sensitize cancer cells and increase the efficacy of standard chemotherapeutic agents. However, the effect of curcumin on the chemoresistancegenerating ability of M2 TAMs is not known.
Objective:
The study aimed to determine whether curcumin could modulate M2 macrophages and suppress their ability to induce resistance to paclitaxel in breast cancer cells.
Methods:
THP-1 cells were differentiated to M2 macrophages using PMA and IL-4/IL-13 in the presence or absence of curcumin in vitro. The effect of the conditioned medium of M2 macrophages on inducing resistance towards paclitaxel in MCF-7 or MDA-MB-231 cells was analyzed by cell proliferation assay, cell cycle analysis, wound healing and transwell migration assays. RT-PCR analysis was used to determine the mRNA expression of anti-inflammatory cytokines in M2 macrophages. The effect of curcumin on TGF-β, pAKT, and pSTAT3 in M2 macrophages was analyzed by western blotting.
Results:
Our data revealed that the M2 macrophages polarized in the presence of curcumin lacked the ability to generate chemoresistance to paclitaxel in breast cancer cell lines. Transcriptomic analysis revealed the expression of TGF-β to be highest amongst M2 macrophage-secreted cytokines. We observed that purified recombinant TGF-β generated chemoresistance in breast cancer cells. We found that curcumin treatment abrogated the expression of TGF-β in M2 macrophages and suppressed their ability to induce chemoresistance in breast cancer cells. STITCH analysis showed strong interaction between curcumin and AKT/STAT3 pathway. Mechanistically, curcumin inhibited PI3K/AKT/STAT3 signaling in M2 macrophages. Western blot analysis revealed that M2 TAM CM, but not curcumin-treated macrophage CM, activated COX2/NF-κB in breast cancer cells.
Conclusion:
Our results showed that curcumin reduced the chemoresistance-generating ability of M2 TAMs. The study has revealed a non-cancer cell-autonomous mechanism by which curcumin partly overcomes the chemoresistance of paclitaxel in breast cancer.
Insights
Curcumin can reduce the chemoresistance of breast cancer cells by modulating M2 tumor-associated macrophages (TAMs). This study shows curcumin inhibits M2 TAMs from inducing paclitaxel resistance, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Breast cancer is a leading cause of cancer mortality in women globally.
- Chemoresistance in breast cancer, often driven by M2 tumor-associated macrophages (TAMs), leads to recurrence and mortality.
- Curcumin is known to enhance chemotherapy efficacy, but its effect on M2 TAMs is unexplored.
Purpose of the Study:
- To investigate if curcumin can modulate M2 macrophages.
- To determine if curcumin suppresses M2 macrophage-induced chemoresistance to paclitaxel in breast cancer cells.
Main Methods:
- THP-1 cells were differentiated into M2 macrophages with or without curcumin.
- The impact of M2 macrophage-conditioned medium on paclitaxel resistance in breast cancer cells was assessed via proliferation, cell cycle, migration, and wound healing assays.
- Gene and protein expression of cytokines (e.g., TGF-β) and signaling pathways (e.g., AKT, STAT3) were analyzed using RT-PCR and Western blotting.
Main Results:
- Curcumin-treated M2 macrophages lost their ability to induce paclitaxel resistance in breast cancer cells.
- Curcumin abrogated TGF-β expression in M2 macrophages, a key cytokine driving chemoresistance.
- Curcumin inhibited the PI3K/AKT/STAT3 signaling pathway in M2 macrophages and suppressed their activation of COX2/NF-κB in breast cancer cells.
Conclusions:
- Curcumin effectively reduces the chemoresistance-conferring ability of M2 TAMs.
- Curcumin offers a non-cancer cell-autonomous mechanism to overcome paclitaxel resistance in breast cancer.
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