Introduction
Resistin, discovered in 2001 by Dr. Mitchell Lazar's group, emerged as a crucial molecule linking diabetes and obesity. The initial research highlighted its role in mediating insulin resistance, earning it the name "Resistin." Despite its relatively recent discovery, resistin has since been implicated in a wide array of physiological and pathological processes, ranging from inflammation to cancer.
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Fig. 1 Disorders associated with increased resistin condition (Deb A, et al. 2021).
Resistin Overview: Sources and Characteristics
Resistin, a ~12.5 KDa pro-inflammatory cytokine, is primarily secreted from macrophages in humans while adipocytes are the major source in rodents. The protein-coding gene RETN encodes this cysteine-rich hormone. Human serum resistin ranges between 7 and 22 ng/ml, forming higher-order oligomers under certain pathophysiological conditions, particularly in autoimmune diseases, metabolic disorders, and cancers.
Interestingly, the human resistin protein comprises 108 amino acids, whereas the rodent homolog contains 114. Only 59% similarity exists between the sequences of human and mice resistin, compelling secondary structural differences-human resistin predominantly exhibits α-helices, while β-sheets characterize mouse resistin.
Resistin and Cancer
Cancer remains one of the most devastating diseases worldwide. Pre-clinical and clinical studies have demonstrated elevated serum resistin levels in patients with various cancers, particularly those influenced by obesity like breast and colon cancers, as well as cancers independent of obesity, including lung and renal cancers. Resistin's role in cancer is multifaceted, contributing to increased risk of progression, angiogenesis, and metastasis in several cancer models. Additionally, resistin is linked to chemoresistance and cancer stemness induction, necessitating further mechanistic studies.
Resistin as a Biomarker
Biomarkers are measurable characteristics indicative of disease states, useful for early diagnosis and understanding treatment regimes. Resistin is emerging as a potential prognostic and diagnostic biomarker in cancer. Studies depict high serum resistin levels in patients with breast cancer, lymphoma, esophageal squamous cell carcinoma, endometrial adenocarcinoma, and gastric and colorectal cancer.
Proliferation and Arrest
Resistin influences cancer proliferation through various signaling pathways, including TLR4, PI-3K, and NFκβ. For example, prostate cancer progression is driven by the AKT pathway, lung cancer by PI-3K and NFκβ pathways, and melanoma by pAKT and Cav-1 pathways. In breast cancer, resistin-induced progression involves IL-6 dependent STAT 3 signaling. Resistin also impacts ovarian cancer progression via miR let-7a, miR-200c, and miR-186. Moreover, in gastric cancer cells, resistin and visfatin synergistically increase cell proliferation by activating the telomerase gene.
Angiogenesis
Resistin promotes angiogenesis by regulating several pathways. In chondrosarcoma cells, it induces VEGF-A expression through the PI3K/Akt pathway, reducing miR-16-5p expression. In ovarian cancer cells, resistin-induced VEGF expression occurs via the PI3K/Akt-Sp1 pathway. In osteosarcoma cells, angiogenesis is driven by ERK, JNK, and p38 pathways, causing VEGF-mediated tube formation.
Metastasis
High resistin levels correlate with increased metastasis in cancer. Endometrial cancer patient studies show significantly higher serum resistin, similar in gastroesophageal and postmenopausal breast cancer patients with distant metastasis. In breast cancer cells, resistin induces phosphorylation of c-src and other molecules, promoting invasion and metastasis by enhancing MMP-2 expression and suppressing miR-519d. Various pathways, including Src/EGFR, NFκB, and PI3K, are involved in lung cancer invasion and migration upon resistin exposure. Additionally, tumor-associated dendritic cells (TADCs) secrete resistin, upregulating Twist in lung cancer cells, inducing EMT.
Chemotherapy Resistance
Resistin's impact on chemotherapy is a developing research area. Increased resistin levels induce resistance to drugs like Gemcitabine in pancreatic cancer and Doxorubicin in breast cancer. Resistin exposure promotes doxorubicin resistance by inducing autophagy via AMPK/mTOR/ULK1 and JNK pathways. In ovarian cancer, high resistin levels correlate with poor prognosis and cisplatin resistance by increasing cancer cell stemness. Additionally, resistin makes colon cancer cells resistant to 5-fluorouracil by G1 phase cell arrest. Resistin inhibits chemotherapy-induced cleavage of caspases in multiple myeloma by activating NFκB and PI3K/Akt pathways.
Resistin and Immunological Disorders
As a pro-inflammatory cytokine, resistin significantly influences immune functions in pathological conditions. It modulates the secretion profile of factors like ICAM-1, VCAM-1, MCP-1, and CCL2 in human macrophages during inflammation, thereby promoting chemotaxis and leukocyte recruitment. Resistin exhibits autocrine, paracrine, and endocrine effects on a broad range of cells by increasing the Th1 immune response and directly activating the complement system. For instance, resistin stimulates the synthesis and secretion of pro-inflammatory cytokines like TNF-α, IL-1, and IL-6 by inducing nuclear translocation of NFκB, which in turn increases IL-8 and MCP-1 production.
Sepsis
Elevated levels of resistin have been reported in patients with sepsis or septic shock, marking the first instance of resistin being identified as a biomarker for disease severity and prolonged inflammation in critically ill patients. Sepsis-induced immunosuppression is a key factor contributing to morbidity and mortality among these patients, with polymorphonuclear neutrophil dysfunction being a hallmark.
Rheumatoid Arthritis
Resistin levels are significantly elevated in the synovial fluid of rheumatoid arthritis patients, contributing to osteoclastogenesis and weak pre-osteoblast differentiation. Resistin increases the pathogenesis of rheumatoid arthritis by inducing chemokines like CXCL1 and CXCL8. It co-localizes with macrophages, B-lymphocytes, and plasma cells, suggesting its pathogenicity in arthritis conditions.
Cardiovascular Disorders
Despite numerous reports on resistin as an important predictor of cardiovascular diseases, its relationship remains controversial. Elevated resistin levels correlate with a surrogate marker of atherosclerosis, the coronary calcium score. Resistin plays a critical role in cardiovascular conditions like myocardial infarction, heart failure, and ischemic events. Hyperresistenimia increases the incidence of cardiovascular diseases, influencing ischemia-perfusion injury, reduced contractility, and hypertrophy.
Resistin and Metabolic Disorders
Obesity
Despite resistin's complex role in obesity, studies indicate that resistin levels increase with obesity, contributing to low-grade chronic inflammation and insulin resistance. The expression of resistin is closely tied to immune cell interactions, particularly with macrophages in adipose tissue. CAP1, identified as a receptor for resistin in adipose tissues, plays a significant role in resistin's action.
Diabetes
Resistin is a critical factor in obesity-associated diabetes (Type 2 Diabetes Mellitus, T2DM). It regulates hepatic glucose production and blood glucose levels by antagonizing insulin action. Elevated resistin levels correlate with glucose intolerance, hyperglycemia, and renal alterations in diabetic patients. It also influences insulin signaling pathways and gene expression related to glucose metabolism.
Hypercholesterolemia
Resistin's role in hypercholesterolemia involves the promotion of lipid accumulation and the formation of foam cells in macrophages. It stimulates PCSK9 expression, leading to LDL receptor degradation and increased cholesterol levels. Dietary and genetic factors significantly impact resistin's role in lipid metabolism, emphasizing its importance in managing hypercholesterolemia and related conditions.
Conclusion
Resistin's diverse roles in inflammation, metabolic regulation, and cancer highlight its significance as a multifunctional molecule. While significant progress has been made in understanding its biological functions, many questions remain unanswered. Future research should focus on unraveling the detailed mechanisms of resistin's action, its interactions with other molecules, and its potential as a therapeutic target. Given its involvement in various pathological conditions, resistin represents a promising biomarker and therapeutic target that could have far-reaching implications for the diagnosis and treatment of numerous diseases.
References
- Deb A., et al. Resistin: A journey from metabolism to cancer. Translational Oncology. 2021, 14 (10): 101178.
- Tripathi D., et al. Resistin in metabolism, inflammation, and disease. The FEBS Journal. 2020, 287 (15): 3141-3149.
- Steppan C. M., et al. The hormone resistin links obesity to diabetes. Nature. 2001, 409 (6818): 307-312.
- Al Hannan F., Culligan K G. Human resistin and the RELM of Inflammation in diabesity. Diabetology & Metabolic Syndrome. 2015, 7: 1-11.
- Jamaluddin M. S., et al. Resistin: functional roles and therapeutic considerations for cardiovascular disease. British Journal of Pharmacology. 2012, 165 (3): 622-632.
- Codoñer-Franch P., Alonso-Iglesias E. Resistin: insulin resistance to malignancy. Clinica Chimica Acta. 2015, 438: 46-54.
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