Potential crosstalk of the interleukin‐6–heme oxygenase‐1‐dependent mechanism involved in resistance to lenalidomide in multiple myeloma cells

Abstract

Interleukin (IL)‐6 is one of the most important survival factors in multiple myeloma (MM), and determines the poor prognosis of MM. IL‐6 mainly has a paracrine bone marrow stromal cell origin and an autocrine MM cell origin. As an enzyme having cytoprotective effects, heme oxygenase‐1 (HO‐1) promotes the growth and drug resistance of various malignant tumors. HO‐1 expression levels in bone marrow CD138+ cells of MM patients were significantly higher than those in healthy donors, and positively correlated with both serum IL‐6 and intracellular IL‐6 mRNA expression levels. Culture of U266, RPMI8226 and CD138+ cells with exogenous IL‐6 in vitro induced high HO‐1 expression levels and allowed them to resist lenalidomide. It is hypothesized that this was probably attributable to IL‐6‐mediated activation of the Janus kinase 2–signal transducer and activator of transcription 3 pathway. In contrast, without IL‐6 coculture, enhanced HO‐1 expression in U266, RPMI8226 and bone marrow CD138+ cells from MM patients significantly inreased IL‐6 mRNA expression levels and facilitated autocrine IL‐6 production. The findings were associated with high HO‐1 expression‐enhanced p38 mitogen‐activated protein kinase phosphorylation. Reduced HO‐1 expression sensitized MM cells to lenalidomide. Therefore, we postulated that IL‐6 in the bone marrow microenvironment of MM patients stimulated high HO‐1 expression in MM cells and their resistance to lenalidomide. High HO‐1 expression also stimulated autocrine IL‐6 production, and exacerbated drug resistance and disease. This study supports the use of HO‐1 as a possible marker for both MM prognosis and drug resistance, and as a potential therapeutic target.

HO-1 Induction in Cancer Progression: A Matter of Cell Adaptation

“…The same results are observed in chronic myeloid leukemia resistant to imatinib by induction of autophagy [101,102]. Furthermore, in multiple myeloma the high expression of HO-1 stimulates the autocrine production of IL-6, one of the most important survival factors, and increases drug resistance and disease [103]. …”

Proteoglycans and glycosaminoglycans as regulators of cancer stem cell function and therapeutic resistance

“…Hypoxia and bidirectional myeloma-stroma cell interactions have been identified as factors responsible for Sdc-1 downregulation [25,27]. In contrast, other studies could not find a difference in the stemness-associated properties of Sdc-1 positive and negative multiple myeloma cell populations, showed the presence of Sdc-1 positive rather than negative cells in the multiple myeloma cell (line) SP and in clonogenic cells, enrichment for pathogenetic properties in the Sdc-1 positive cell population, and responsiveness of the Sdc-1-positive cell population to the stemness-associated hedgehog and IL-6 signaling pathways, which were associated with chemotherapeutic resistance [25,28,29]. The kinetics of conversion of a Sdc-1-low into a Sdc-1-positive population and the modulation of Sdc-1 expression and shedding status by the HS-degrading enzyme heparanase may partially account for these seemingly contradictory data [30].…”

HO‐1 downregulation favors BRAFV600 melanoma cell death induced by Vemurafenib/PLX4032 and increases NK recognition

“…Overall, HO-1 metabolic products exert antioxidant, anti-inflammatory and antiapoptotic activities. 5 HO-1 induction has been highlighted as a mechanism involved in cancer progression, playing a role in cancer growth, resistance to therapies, invasiveness, angiogenesis and metastatic potential, with different evidence in many kinds of tumor including multiple myeloma, 6 acute leukemia 7 and neuroblastoma. [8][9][10] Interestingly, it has been proved that the upregulation of HO-1 in cancer cells impairs tumor immune recognition decreasing cell-mediated toxicity.…”