Leptin signaling molecular actions and drug target in hepatocellular carcinoma

Abstract

Previous reports indicate that over 13 different tumors, including hepatocellular carcinoma (HCC), are related to obesity. Obesity-associated inflammatory, metabolic, and endocrine mediators, as well as the functioning of the gut microbiota, are suspected to contribute to tumorigenesis. In obese people, proinflammatory cytokines/chemokines including tumor necrosis factor-alpha, interleukin (IL)-1 and IL-6, insulin and insulin-like growth factors, adipokines, plasminogen activator inhibitor-1, adiponectin, and leptin are found to play crucial roles in the initiation and development of cancer. The cytokines induced by leptin in adipose tissue or tumor cells have been intensely studied. Leptin-induced signaling pathways are critical for biological functions such as adiposity, energy balance, endocrine function, immune reaction, and angiogenesis as well as oncogenesis. Leptin is an activator of cell proliferation and anti-apoptosis in several cell types, and an inducer of cancer stem cells; its critical roles in tumorigenesis are based on its oncogenic, mitogenic, proinflammatory, and pro-angiogenic actions. This review provides an update of the pathological effects of leptin signaling with special emphasis on potential molecular mechanisms and therapeutic targeting, which could potentially be used in future clinical settings. In addition, leptin-induced angiogenic ability and molecular mechanisms in HCC are discussed. The stringent binding affinity of leptin and its receptor Ob-R, as well as the highly upregulated expression of both leptin and Ob-R in cancer cells compared to normal cells, makes leptin an ideal drug target for the prevention and treatment of HCC, especially in obese patients.

Keywords: drug target; hepatocellular carcinoma; leptin; leptin antagonist; leptin signaling; tumor angiogenesis.

Figure 1

Crosstalk between leptin signaling and signaling pathways in HCC. Notes: Leptin binding to the receptor Ob-R in HCC cells activates canonical (JAK2/STAT, MAPK, and PI-3K) signaling pathways. Leptin-induced JAK2/STAT3, MAPK, PI-3K/mTOR, p38, and JNK signaling. PI-3K/Akt induces phosphorylation of mTOR. MAPK activation plays an important role in activating ERK 1/2, p38, and JNK, which in turn induce NF-κB activation. Levels of proinflammatory/pro-angiogenic molecules can also be induced by leptin signaling pathways. Solid and dashed arrows indicate the main and alternative mechanisms of leptin actions. Abbreviations: HCC, hepatocellular carcinoma; JAK2, Janus kinase 2; MAPK, mitogen-activated protein kinase; PI-3K, phosphoinositide 3-kinase; mTOR, mammalian target of rapamycin; Akt, protein kinase B; ERK 1/2, extracellular regulated kinase 1 and 2; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; STAT, signal transducer and activator of transcription; Adip, adipose; Lep, leptin; ER, estrogen receptor.