PPAR agonists attenuate lenalidomide's anti-myeloma activity in vitro and in vivo

Sha, Yi‐Gao; Wu, Jian; Paul, Barry; Zhao, Yue; Mathews, Parker; Li, Zhiguo; Norris, John E.; Wang, Endi; McDonnell, Donald P.; Kang, Yubin

doi:10.1016/j.canlet.2022.215832

Cited by 5 publications

(8 citation statements)

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“…PPARs isoforms can act as pro- or anti-tumorigenic factors. Preclinical or clinical evidence has proven that PPAR agonists or antagonists play critical roles in tumor metabolic reprogramming, cellular environmental homeostasis, and drug response [ 24 , 25 ]. High-fat diet (HFD) was reported to contribute to CRC progression and liver metastasis, and PPARD antagonists could reverse this condition and might be beneficial for CRC treatment [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

SLC27A2 mediates FAO in colorectal cancer through nongenic crosstalk regulation of the PPARs pathway

Shang

Che

et al. 2023

BMC Cancer

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Background Peroxisome proliferator activated receptors (PPARs) are a nuclear hormone receptors superfamily that is closely related to fatty acid (FA) metabolism and tumor progression. Solute carrier family 27 member 2 (SLC27A2) is important for FA transportation and metabolism and is related to cancer progression. This study aims to explore the mechanisms of how PPARs and SLC27A2 regulate FA metabolism in colorectal cancer (CRC) and find new strategies for CRC treatment. Methods Biological information analysis was applied to detect the expression and the correlation of PPARs and SLC27A2 in CRC. The protein–protein interaction (PPI) interaction networks were explored by using the STRING database. Uptake experiments and immunofluorescence staining were used to analyse the function and number of peroxisomes and colocalization of FA with peroxisomes, respectively. Western blotting and qRT‒PCR were performed to explore the mechanisms. Results SLC27A2 was overexpressed in CRC. PPARs had different expression levels, and PPARG was significantly highly expressed in CRC. SLC27A2 was correlated with PPARs in CRC. Both SLC27A2 and PPARs were closely related to fatty acid oxidation (FAO)‒related genes. SLC27A2 affected the activity of ATP Binding Cassette Subfamily D Member 3 (ABCD3), also named PMP70, the most abundant peroxisomal membrane protein. We found that the ratios of p-Erk/Erk and p-GSK3β/GSK3β were elevated through nongenic crosstalk regulation of the PPARs pathway. Conclusions SLC27A2 mediates FA uptake and beta-oxidation through nongenic crosstalk regulation of the PPARs pathway in CRC. Targeting SLC27A2/FATP2 or PPARs may provide new insights for antitumour strategies.

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Section: Discussionmentioning

confidence: 99%

SLC27A2 mediates FAO in colorectal cancer through nongenic crosstalk regulation of the PPARs pathway

Shang

Che

et al. 2023

BMC Cancer

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“…However, it remains unclear how CRBN is regulated and whether different genomic approaches or drugs could affect sensitivity to IMiDs through the regulation of CRBN expression. We have previously shown that PPARs agonists (fenofibrate, GW501516, and troglitazone) reduce the anti-myeloma effect of lenalidomide by downregulating the transcription activity of CRBN, while PPARs antagonists (GW3787, GW9662, and GW6471) increase CRBN expression and improve lenalidomide activity [ 53 ]. Promoter binding analysis based on the Chip assay and luciferase assay suggested that there are different PPAR binding sites on the CRBN promoter region; therefore, PPARs regulate CRBN transcriptional activity by stimulating these sites [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

“…We have previously shown that PPARs agonists (fenofibrate, GW501516, and troglitazone) reduce the anti-myeloma effect of lenalidomide by downregulating the transcription activity of CRBN, while PPARs antagonists (GW3787, GW9662, and GW6471) increase CRBN expression and improve lenalidomide activity [ 53 ]. Promoter binding analysis based on the Chip assay and luciferase assay suggested that there are different PPAR binding sites on the CRBN promoter region; therefore, PPARs regulate CRBN transcriptional activity by stimulating these sites [ 53 ]. In this study, we explored the exact mechanism of this transcriptional inhibition of CRBN by PPARs.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic Studies and a Retrospective Cohort Study: The Interaction between PPAR Agonists and Immunomodulatory Agents in Multiple Myeloma

Chu

Paul

et al. 2022

Cancers

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Our previous study demonstrated that peroxisome proliferator-activated receptor (PPAR) agonists downregulated cereblon (CRBN) expression and reduced the anti-myeloma activity of lenalidomide in vitro and in vivo. We aimed to determine whether DNA methylation and protein degradation contribute to the effects of PPAR agonists. CRBN promoter methylation status was detected using methylation-specific polymerase chain reaction. The CRBN protein degradation rate was measured using a cycloheximide chase assay. Metabolomic analysis was performed in multiple myeloma (MM) cells treated with PPAR agonists and/or lenalidomide. Our retrospective study determined the effect of co-administration of PPAR agonists with immunomodulatory drugs on the outcomes of patients with MM. CpG islands of the CRBN promoter region became highly methylated upon treatment with PPAR agonists, whereas treatment with PPAR antagonists resulted in unmethylation. The CRBN protein was rapidly degraded after treatment with PPAR agonists. Lenalidomide and fenofibrate showed opposite effects on acylcarnitines and amino acids. Co-administration of immunomodulatory drugs and PPAR agonists was associated with inferior treatment responses and poor survival. Our study provides the first evidence that PPAR agonists reduce CRBN expression through various mechanisms including inducing methylation of CRBN promoter CpG island, enhancing CRBN protein degradation, and affecting metabolomics of MM cells.

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“…So far, a very few studies have analyzed the role of PPAR β/δ in MM. Whereas two old studies highlighted its ability to decrease myeloma cell growth through the down-regulation of NFκB activity [ 29 , 30 ], two very recent papers demonstrated PPAR β/δ upregulation in the BM CD138+ plasma cells and BM CD138− microenvironment cells in patients with newly diagnosed MM compared with those in normal BM controls, and a higher PPAR β/δ expression was associated with worse progression-free survival (PFS) and overall survival (OS) [ 31 , 32 ]. Moreover, Wu et al investigated the drug–drug interactions between immunomodulatory agents (IMiDs) and PPAR agonists in patients with MM, demonstrating opposite metabolic effects of these molecules in MM cells [ 32 ].…”

Section: Introductionmentioning

confidence: 99%

Unraveling the Role of Peroxisome Proliferator-Activated Receptor β/Δ (PPAR β/Δ) in Angiogenesis Associated with Multiple Myeloma

Leone

Solimando

Prete

et al. 2023

Cells

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Growing evidence suggests a role for peroxisome proliferator-activated receptor β/δ (PPAR β/δ) in the angiogenesis, growth, and metastasis of solid tumors, but little is known about its role in multiple myeloma (MM). Angiogenesis in the bone marrow (BM) is characteristic of disease transition from monoclonal gammopathy of undetermined significance (MGUS) to MM. We examined the expression and function of PPAR β/δ in endothelial cells (EC) from the BM of MGUS (MGEC) and MM (MMEC) patients and showed that PPAR β/δ was expressed at higher levels in MMEC than in MGEC and that the overexpression depended on myeloma plasma cells. The interaction between myeloma plasma cells and MMEC promoted the release of the PPAR β/δ ligand prostaglandin I2 (PGI2) by MMEC, leading to the activation of PPAR β/δ. We also demonstrated that PPAR β/δ was a strong stimulator of angiogenesis in vitro and that PPAR β/δ inhibition by a specific antagonist greatly impaired the angiogenic functions of MMEC. These findings define PGI2-PPAR β/δ signaling in EC as a potential target of anti-angiogenic therapy. They also sustain the use of PPAR β/δ inhibitors in association with conventional drugs as a new therapeutic approach in MM.

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PPAR agonists attenuate lenalidomide's anti-myeloma activity in vitro and in vivo

Cited by 5 publications

References 82 publications

SLC27A2 mediates FAO in colorectal cancer through nongenic crosstalk regulation of the PPARs pathway

SLC27A2 mediates FAO in colorectal cancer through nongenic crosstalk regulation of the PPARs pathway

Mechanistic Studies and a Retrospective Cohort Study: The Interaction between PPAR Agonists and Immunomodulatory Agents in Multiple Myeloma

Unraveling the Role of Peroxisome Proliferator-Activated Receptor β/Δ (PPAR β/Δ) in Angiogenesis Associated with Multiple Myeloma

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