2. Academic Validation
  3. Palmitic acid inhibits macrophage-mediated chemotherapy resistance in multiple myeloma via ALOX12 signaling

Palmitic acid inhibits macrophage-mediated chemotherapy resistance in multiple myeloma via ALOX12 signaling

  • Int Immunopharmacol. 2024 Dec 25;143(Pt 1):113320. doi: 10.1016/j.intimp.2024.113320.
He Dong 1,  Jintong Chen 2,  Hua Zhang 3,  Munan Zhao 4,  Ying Yue 5,  Siqing Wang 6
Affiliations

Affiliations

  • 1 Department of Gynecological Oncology, The First Hospital of Jilin University, Changchun 130021, China.
  • 2 Department of Hematology, The First Hospital of Jilin University, Changchun 130021, China.
  • 3 Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun 130021, China.
  • 4 Stem Cell and Cancer Center, The First Hospital of Jilin University, Changchun, 130021, China.
  • 5 Department of Gynecological Oncology, The First Hospital of Jilin University, Changchun 130021, China. Electronic address: yuey@jlu.edu.cn.
  • 6 Department of Cancer Immunology, The First Hospital of Jilin University, Changchun 130061, China. Electronic address: wkerger@jlu.edu.cn.
PMID: 39378653 DOI: 10.1016/j.intimp.2024.113320
Abstract

We previously discovered that macrophages (MΦs), especially tumor-associated MΦs (tMΦs), contribute to chemotherapy resistance in multiple myeloma (MM). However, the mechanism underlying MΦ-mediated chemotherapy resistance in MM needs further elucidation, and the identification of factors that preferentially abrogate MΦ-induced inhibition of MM chemotherapy may have important clinical significance. In this study, we showed that the expression of FASN and SCD2, the Enzymes that synthesize palmitic acid and convert it to palmitoleic acid, was decreased in tMΦs compared with MΦs. Interestingly, palmitic acid abrogated the MΦ-mediated protection of MM cells from the effects of bortezomib and melphalan in vitro. Combination treatment with palmitic acid and bortezomib or melphalan further inhibited MM tumor growth in vivo. Mechanistically, palmitic acid treatment increased ALOX12 expression in MΦs. ALOX12 inhibition partially abrogated the palmitic acid-induced decrease in MΦ-mediated MM cell survival. Palmitic acid treatment inhibited AMPK signaling in MΦs, and ALOX12 knockdown activated the AMPK signaling pathway in MΦs. AMPK inhibition decreased the MΦ-mediated protection of drug-treated MM cells, and AMPK activation partially abolished the palmitic acid-induced inhibition of MΦ-mediated protection. ALOX12 converts arachidonic acid (AA) to 12-HETE. Moreover, treatment with AA but not 12-HETE partially abrogated the inhibitory effect of palmitic acid on MΦ-mediated MM cell survival in response to bortezomib or melphalan. Overall, we identified palmitic acid as a factor that inhibits MΦ-mediated resistance to bortezomib and melphalan in MM, which may have clinical significance.

Keywords

ALOX12; Chemotherapy resistance; Macrophage; Multiple myeloma; Palmitic acid.

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