Title:Curcumin Suppresses M2 Macrophage-derived Paclitaxel Chemoresistance through
Inhibition of PI3K-AKT/STAT3 Signaling
Volume: 24
Issue: 2
Author(s): Bhawna Deswal, Urmi Bagchi and Sonia Kapoor*
Affiliation:
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida, Uttar Pradesh, 201313, India
Keywords:
Tumor-associated macrophages, breast cancer, curcumin, chemoresistance, TGF-β, paclitaxel chemoresistance.
Abstract:
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.
