Resistin induces multidrug resistance in myeloma by inhibiting cell death and upregulating ABC transporter expression

Abstract

Despite advances in therapy, multiple myeloma remains incurable, with a high frequency of relapse. This suggests the need to identify additional factors that contribute to drug resistance. Our previous studies revealed that bone marrow adipocytes promote resistance to chemotherapy in myeloma through adipocyte-secreted adipokines, but the mechanism underlying this effect and the specific adipokines involved are not well understood. We proposed to determine the role of resistin, an adipokine that is secreted by adipocytes, in chemotherapy resistance in myeloma. We found that resistin abrogated chemotherapy-induced apoptosis in established myeloma cell lines and primary myeloma samples. Resistin inhibited chemotherapy-induced caspase cleavage through the NF-κB and PI3K/Akt pathways. Resistin also increased the expression and drug efflux function of ATP-binding cassette (ABC) transporters in myeloma cells through decreasing the expression of both DNA methyltransferases DNMT1 and DNMT3a and the methylation levels of ABC gene promoters. In vivo studies further demonstrated the protective effect of resistin in chemotherapy-induced apoptosis. Our study thus reveals a new biological function of resistin in the pathogenesis of myeloma, with the implication that targeting resistin could be a potential strategy to prevent or overcome multidrug resistance in myeloma.

Retracted: Resistin effects on pancreatic cancer progression and chemoresistance are mediated through its receptors CAP1 and TLR4

“…One of the important functions attributed to resistin signaling is its ability to induce resistance to chemotherapy (Liu et al, ; Pang et al, ; Slomian et al, ). We, therefore, checked for such activity of resistin in pancreatic cancer cells.…”

“…In the initial reports published about a decade back, resistin was evaluated in breast (Kang, Yu, & Youn, ), prostate (Housa et al, ), lung (Karapanagiotou et al, ), colorectal (Wagsater, Mumtaz, Lofgren, Hugander, & Dimberg, ), and gastric (Nakajima et al, ) cancers and the overall impression was that it is a factor worth further studies and there were observations supporting its possible use as a diagnostic marker, expression levels of which also seemed to differ in patients with varying clinical stages. In the last decade, resistin has been studied in endometrial (Hlavna et al, ), chondrosarcoma (Tsai et al, ), myeloma (Pang et al, ), and renal (Kallio et al, ) cancer models, in addition to many more reports in cancers mentioned above.…”

Bone Marrow Stromal Cells-Induced Drug Resistance in Multiple Myeloma

“…Adipocytes residing in the BM directly interact with myeloma plasma cells [39] and protect them against apoptosis induced by anti-myeloma chemotherapy [85][86][87]. MM plasma cells induce BM resident adipocytes to release lipids, which are subsequently utilized as energy for tumor cell proliferation [39].…”

“…MM plasma cells induce BM resident adipocytes to release lipids, which are subsequently utilized as energy for tumor cell proliferation [39]. Moreover, adipocytes produce and secrete adipokines, that stimulate MM plasma cell growth through activating JAK/STAT-PI3K/AKT pathway [87], and resistin, which inhibits myeloma cell apoptosis and promotes ATP-binding cassette (ABC) transporters expression [86]. ABC overexpression is a well-known mechanism of multidrug resistance in various cancers [88].…”

Adipokines, adiposity, and bone marrow adipocytes: Dangerous accomplices in multiple myeloma

“…Low resistin levels were found to be associated with increased risk (Dalamaga et al, ) particularly in men (Santo et al, ). However, Pang et al, () demonstrated that resistin could play a role in drug resistance, abrogating chemotherapy‐induced apoptosis in myeloma cells via the inhibition of chemotherapy‐induced caspase cleavage. Taken together these two studies suggest that resistin could be protective against early stages of disease development, whereas detrimental in later stage.…”