Leptin signaling and cancer chemoresistance: Perspectives

Abstract

Obesity is a major health problem and currently is endemic around the world. Obesity is a risk factor for several different types of cancer, significantly promoting cancer incidence, progression, poor prognosis and resistance to anti-cancer therapies. The study of this resistance is critical as development of chemoresistance is a serious drawback for the successful and effective drug-based treatments of cancer. There is increasing evidence that augmented adiposity can impact on chemotherapeutic treatment of cancer and the development of resistance to these treatments, particularly through one of its signature mediators, the adipokine leptin. Leptin is a pro-inflammatory, pro-angiogenic and pro-tumorigenic adipokine that has been implicated in many cancers promoting processes such as angiogenesis, metastasis, tumorigenesis and survival/resistance to apoptosis. Several possible mechanisms that could potentially be developed by cancer cells to elicit drug resistance have been suggested in the literature. Here, we summarize and discuss the current state of the literature on the role of obesity and leptin on chemoresistance, particularly as it relates to breast and pancreatic cancers. We focus on the role of leptin and its significance in possibly driving these proposed chemoresistance mechanisms, and examine its effects on cancer cell survival signals and expansion of the cancer stem cell sub-populations.

The Role of Notch Signaling and Leptin-Notch Crosstalk in Pancreatic Cancer

“…A wide-used PC drug, gemcitabine, increased PCSC expressing CD24+ and CD133+, stemness-associated genes (Bmi1, Nanog, and Sox2), cell migration, chemoresistance, and tumorigenesis [ 51 ]. Gemcitabine induced PCSC overexpressing ABCB1 and CD44+ that correlated with higher tumor histological grade and worse prognosis [ 3 ]. Moreover, Notch2, Notch4 and JAG1 overexpression correlated with PC-Gemcitabine chemoresistance [ 70 ].…”

“…It is known that leptin and Notch signaling mediate the activation of cancer stem cells that can affect drug resistance [ 3 , 54 , 95 ]. We have further shown that leptin and its receptor OB-R are expressed on PC cells, establishing an autocrine/paracrine signaling loop [ 37 ].…”

“…Notch signaling has been recently linked to 5-FU resistance in PC [ 2 ]. This embryonic signaling pathway controls the maintenance and proliferation of the stem cell niche, cell fate decisions and can drive carcinogenesis [ 3 ]. The family of Notch receptors includes four transmembrane proteins (Notch1–4), which are activated upon interaction with different types of ligands [Serrate-like Jagged1 and 2 (JAG1–2) and Delta-like (Delta1–4)] expressed by adjacent cells.…”

Leptin promotes expression of EMT-related transcription factors and invasion in a Src and FAK-dependent pathway in MCF10A mammary epithelial cells

“…The overexpression of leptin and its receptor, the ObR, has been associated to tumor progressionrelated events in breast cancer [4][5][6]. Leptin exerts its effects through binding with the ObR receptor, promoting the activation of several signaling pathways such as MAPK, PI3K/AKT and JAK/STAT [3,7,8]. The signaling pathways activated by leptin regulate cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) [4,5,[9][10][11].…”

Long Non-Coding RNAs in Obesity-Induced Cancer

“…Anti-apoptotic and mitogenic effects of leptin have been demonstrated on different cancer cell lines [ 19 ]. From reports, the significantly high circulating level of leptin is associated with enhanced cell proliferation and increased risks of cancers in the leptin resistance in obese subjects [ 20 , 21 , 22 ].…”