Leptin-Induced JAK/STAT Signaling and Cancer Growth

Abstract

Growth factor and cytokine signaling can influence the development of several cancer types. One of the key players in the development of cancer is the Janus kinas (JAK) signal transducer of activators of transcription (STAT) signaling pathway. The majority of growth factors and cytokine interactions with their membrane-bound receptors trigger JAK-STAT activation. The influential relationship between obesity and cancer is a fact. However, there is a complex sequence of events contributing to the regulation of this mechanism to promote tumor growth, yet to be fully elucidated. The JAK-STAT pathway is influenced by obesity-associated changes that have been shown to impact cancer growth and progression. This intricate process is highly regulated by a vast array of adipokines and cytokines that exert their pleiotropic effects on cancer cells to enhance metastasis to distant target sites. Leptin is a cytokine, or more precise, an adipokine secreted mainly by adipose tissue that requires JAK-STAT activation to exert its biological functions. Leptin is the central regulator of energy balance and appetite. Leptin binding to its receptor OB-R in turn activates JAK-STAT, which induces proliferation, angiogenesis, and anti-apoptotic events in normal cells and malignant cells expressing the receptor. Leptin also induces crosstalk with Notch and IL-1 (NILCO), which involves other angiogenic factors promoting tumor growth. Therefore, the existence of multiple novel classes of therapeutics that target the JAK/STAT pathway has significant clinical implications. Then, the identification of the signaling networks and factors that regulate the obesity-cancer link to which potential pharmacologic interventions can be implemented to inhibit tumor growth and metastasis. In this review, we will discuss the specific relationship between leptin-JAK-STAT signaling and cancer.

Leptin signaling and cancer chemoresistance: Perspectives

“…Because Class I cytokine receptors lack auto phosphorylation function they need auxiliary kinases to initiate signaling upon ligand binding. The first signaling event after leptin binding to Ob-Rb is the activation of janus kinase/signaling transducer and activation of transcription factor pathway (JAK/STAT)[21]. JAK2 recruitment to Ob-R intracytoplasmatic tail leads to the phosphorylation of the kinase, subsequent phosphorylation of Ob-R in several intracytoplasmatic sites and recruitment and phosphorylation of tyrosine residue on STATs.…”

Translational opportunities for broad‐spectrum natural phytochemicals and targeted agent combinations in breast cancer

“…Obesity associated circulating factors induce over activation of IGF1R pathway and increased oxidative stress which together lead to activation of MAPK, PIP3 and mTOR pathways . Obesity leads to higher levels of leptin which promotes BC progression through JAK/STAT3 and estrogen pathways . The adipose derived stromal cells (ADSCs) harbor leptin receptors and mediate estrogenic effects in response to paracrine and/or autocrine stimulation by leptin .…”

“…66 Obesity leads to higher levels of leptin which promotes BC progression through JAK/ STAT3 and estrogen pathways. 67 The adipose derived stromal cells (ADSCs) harbor leptin receptors and mediate estrogenic effects in response to paracrine and/or autocrine stimulation by leptin. [68][69][70] The aromatase, which is involved in E2 synthesis, is mainly expressed in adipose tissue.…”

Pancreatic Cancer and Obesity: Some Molecular Perspectives

“…Once this signaling pathway is fully elucidated, the effects of obesity (leptin)-mediated regulation of RBP-Jk, and its impact on cancer progression may have clinical implications. It is envisaged that meticulous investigations in adipocyte biology, tumor microenvironment and obesity-related cancer will lead to the identification of new therapeutic targets for cancer and metabolic diseases [40].…”