Growth differentiation factor 15 in cancer cachexia (Review)

Roles and mechanisms of GDF15 in CC. Solid lines indicate demonstrated mechanisms and dashed lines indicate possible mechanisms. GDF15 initiates the phosphorylation of ERK, Akt and PLCγ via GFRAL/RET signaling to mediate anorexia, muscle atrophy and fat loss in CC; the antibody 3P10 can inhibit these processes. Binding of GDF15 to TGFβRII and TGFβRI leads to the phosphorylation of ERK1/2 and STAT3. This pathway downregulates NPY and upregulates POMC to induce anorexia. Reduced food intake indirectly contributes to muscle wasting and fat depletion in cancer cachexia. Activation of MAP3K11/GDF15 and Bcl-2/caspase-3 apoptotic pathways is responsible for CC muscle atrophy, but their specific receptors are unknown. GDF15 may also reduce muscle mass through the TAK-1/NF-κB signaling pathway, and downregulates the expression of miR-1, miR-133a and miR-499 in muscle. In addition, GDF15 may promote muscle atrophy and fat loss by stimulating the HPA axis. Moreover, the GDF15/Smad2/3 pathway may be involved in CC-induced anemia. High levels of GDF15 directly inhibit the expression of hepcidin, which could further trigger anemia and muscle wasting in CC. GDF15, growth differentiation factor 15; CC, cancer cachexia; ERK, extracellular signal-regulated kinase; PLCγ, phospholipase C γ; GFRAL, glial cell-derived neurotrophic factor receptor α-like; RET, ret proto-oncogene; TGFβRII, type II transforming growth factor-β receptor; TGFβRI, type I transforming growth factor-β receptor; ERK1/2, extracellular signal-regulated kinase1/2; STAT3, signal transducer and activator of transcription 3; NPY, neuropeptide Y; POMC, pro-opiomelanocortin; MAP3K11, mitogen-activated protein kinase 11; Bcl-2, B cell lymphoma-2; TAK-1, transforming growth factor-β-activating kinase-1; NF-κB, nuclear factor-κB; miR, microRNA; HPA, hypothalamus-pituitary-adrenal; CRH, corticotropin-releasing hormone; GC, glucocorticoids; ZAG, zinc-α2-glycoprotein; β3-AR, β3-adrenergic receptor; MuRF1, muscle ring finger 1; Bax, Bcl-2 associated X protein; RANK, receptor activation of NF-κB; RANKL, RANK ligand; CCL2, CC motif chemokine ligand 2; p, phosphorylation.

Publication

Role of growth differentiation factor 15 in cancer cachexia (Review). (2023) Tingting Ling, et al. Oncol Lett. 2023 Nov;26(5):462. Figure: F4. Homo sapiens

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