Adipocytes secreted leptin is a pro-tumor factor for survival of multiple myeloma under chemotherapy

Abstract

Accumulating evidences have shown that adipokines secreted from adipocytes contributes to tumor development, especially leptin. However, underlying mechanisms remain unclear. This study aims to explore the effect of leptin on development and chemoresistance in multiple myeloma cells and the potential mechanism. Analysis of levels of adipokines including leptin and adiponectin in 28 multiple myeloma patients identified significantly higher leptin compared with 28 normal controls(P < 0.05), and leptin level was positively correlated with clinical stage, IgG, ER, and ß2MG. Next, by using co-culture system of myeloma and adipocytes, and pharmacologic enhancement of leptin, we found that increased growth of myeloma cells and reduced toxicity of bortezomib were best observed at 50 ng/ml of leptin, along with increased expression of cyclinD1, Bcl-2 and decreased caspase-3 expression. We also found that phosphorylated AKT and STAT3 but not the proteins expression reached peak after 1h and 6h treatment of leptin, respectively. By using AG490, an agent blocking the phosphorylation of AKT and ERK, the proliferation of myeloma cells was inhibited, as well as the phosphorylation of AKT and STAT3, even adding leptin. Taken together, our study demonstrated that up-regulated leptin could stimulate proliferation of myeloma and reduce the anti-tumor effect of chemotherapy possibly via activating AKT and STAT3 pathways, and leptin might be one of the potential therapeutic targets for treating myeloma.

The potential role of leptin in tumor invasion and metastasis

“…Anti-apoptotic effect of leptin in cancer is a frequent observation of many investigators [181–185]. Similarly, several reports have documented that leptin can facilitate the formation of new blood vessels or angiogenesis, along with biosynthesis of pro-angiogenic factors like VEGF [185–187].…”

Reflections on Cancer in the Bone Marrow: Adverse Roles of Adipocytes

“…Other researchers later confirmed that leptin induces myeloma proliferation. For example, in one study researchers analyzed levels of adipokines including leptin and adiponectin in 28 MM patients and identified significantly higher leptin compared with controls [23]. Leptin levels were positively correlated with clinical stage, bone marrow plasma cells percentage, and levels of immunoglobulin G (IgG), beta-2 microglobulin (β2MG), and erythrocyte sedimentation rate [23].…”

“…For example, in one study researchers analyzed levels of adipokines including leptin and adiponectin in 28 MM patients and identified significantly higher leptin compared with controls [23]. Leptin levels were positively correlated with clinical stage, bone marrow plasma cells percentage, and levels of immunoglobulin G (IgG), beta-2 microglobulin (β2MG), and erythrocyte sedimentation rate [23]. In MM cell and adipocyte co-culture, increased growth of myeloma cells and reduced toxicity of bortezomib were observed, along with increased expression of cyclinD1, B-cell lymphoma 2 (Bcl-2) and decreased caspase-3 expression.…”

“…In MM cell and adipocyte co-culture, increased growth of myeloma cells and reduced toxicity of bortezomib were observed, along with increased expression of cyclinD1, B-cell lymphoma 2 (Bcl-2) and decreased caspase-3 expression. Phosphorylated protein kinase B (AKT) and Signal transducer and activator of transcription 3 (STAT3) were stimulated by leptin treatment and leptin signaling via these pathways induced myeloma cell proliferation [23]. Overall, it appears that leptin might be a potential therapeutic target for treating myeloma.…”

MicroRNA Transfer Between Bone Marrow Adipose and Multiple Myeloma Cells

“…Myeloma is the second most common hematological malignancy worldwide, affecting nearly 100,000 people in the United States alone, and remains incurable [2, 3]. The bone marrow microenvironment (BMME), an intricate and dynamic niche composed of extracellular matrix (ECM) proteins and cells of hematopoietic lineage, serves as an instrumental contributor to myeloma disease progression [4].…”