Palmitic acid inhibits macrophage-mediated chemotherapy resistance in multiple myeloma via ALOX12 signaling
Year: 2024
Type: article
Abstract: • Palmitic acid inhibits macrophage-induced chemotherapy resistance in multiple myeloma. • Palmitic acid increases the expression of ALOX12 in macrophages. • ALOX12 inhibits p-AMPK signaling in macrophages. • Palmitic acid inhibits macrophage-mediated chemotherapy resistance in multiple myeloma through ALOX12-mediated inhibition of p-AMPK. 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.
Source: International Immunopharmacology
Authors: He Dong, Jintong Chen, Hua Zhang, Munan Zhao, Ying Yue, Siqing Wang
Institution: First Hospital of Jilin University
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,250
OpenAlex ID: W4403226045