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.

Abstract

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.

Related Concept Videos

Drugs that Stabilize Microtubules01:15

Drugs that Stabilize Microtubules

Microtubules are dynamic structures that undergo cycles of catastrophe and rescue. The microtubules play a central role in cell division by forming the spindle apparatus for segregating the chromosomes. This makes them ideal targets for regulating dividing cells in tumors and malignant cancer cells. Microtubule stabilizing drugs help stabilize the microtubule formation and promote its polymerization. Paclitaxel was the first microtubule stabilizing agent used as anticancer drug in chemotherapy...
2.1K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
3.6K
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.5K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.8K
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
6.3K
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
8.9K