A review of Dynamin 2 involvement in cancers highlights a promising therapeutic target

Abstract

Dynamin 2 (DNM2) is an ubiquitously expressed large GTPase well known for its role in vesicle formation in endocytosis and intracellular membrane trafficking also acting as a regulator of cytoskeletons. During the last two decades, DNM2 involvement, through mutations or overexpression, emerged in an increasing number of cancers and often associated with poor prognosis. A wide panel of DNM2-dependent processes was described in cancer cells which explains DNM2 contribution to cancer pathomechanisms. First, DNM2 dysfunction may promote cell migration, invasion and metastasis. Second, DNM2 acts on intracellular signaling pathways fostering tumor cell proliferation and survival. Relative to these roles, DNM2 was demonstrated as a therapeutic target able to reduce cell proliferation, induce apoptosis, and reduce the invasive phenotype in a wide range of cancer cells in vitro. Moreover, proofs of concept of therapy by modulation of DNM2 expression was also achieved in vivo in several animal models. Consequently, DNM2 appears as a promising molecular target for the development of anti-invasive agents and the already provided proofs of concept in animal models represent an important step of preclinical development.

Combinatorial treatment with statins and niclosamide prevents CRC dissemination by unhinging the MACC1-β-catenin-S100A4 axis of metastasis

“…Structurally, the MACC1 molecule serves as a scaffold for MEK1, leading to prolonged and potentiated ERK1 activation [ 8 ]. Furthermore, MACC1 promotes the dynamin-dependent restoration of the growth factor receptor EGFR in the cell membrane [ 9 , 10 ]. These capabilities fuel various cancer hallmarks, such as enhanced survival, proliferation, motility, and metastasis of cancer [ 6 , 11 – 15 ].…”

Role of motor proteins in human cancers

“…c-Met is a tyrosine kinase receptor involved in the development and progression of cancer cells through stimulating the PI3K/AKT, Ras/MAPK, JAK/STAT, SRC, Wnt/β-catenin pathways, among many others. Through increasing degradation of c- Met, Dynamin inhibitors were able to inhibit the c-Met downstream signaling, leading to increased tumor cell apoptosis ( Trochet and Bitoun, 2021 ).…”

“…Dynamin 2 inhibitors were known to inhibit cytokinesis during mitosis, resulting in growth arrest and apoptosis of cancer cells in several cancer cell lines including lung, cervical, and leukemia ( Trochet and Bitoun, 2021 ).…”

Development of versatile allele-specific siRNAs able to silence all the dominant dynamin 2 mutations

“…Rescue of cell migration by AS-siRNA DNM2 dysfunction through its overexpression is known to promote cell migration, invasion, and metastasis in cancers. 12 Therefore, we looked for migration defects in the two fibroblast cell lines carrying the p.R522H and the p.S619L CNM mutations. We have tracked single cells during 24 h and compared the motility behavior in the two patient-derived cell lines and two healthy control cell lines.…”

“…2,3 AD-CNM results from mutations in the DNM2 gene (OMIM: *602378, which encodes dynamin 2 (DNM2). 4 In addition, DNM2 mutations also cause rare forms of Charcot-Marie-Tooth disease (CMT, OMIM: #606482) 5 and hereditary spastic paraplegia (HSP), 6 and a deleterious DNM2 overexpression was reported in several cancers [7][8][9][10][11][12] and the X-linked recessive CNM, 13 highlighting a large DNM2 involvement in human diseases. DNM2 belongs to the superfamily of large GTPases 14 acting as a mechanochemical scaffolding molecule that oligomerizes and deforms biological membranes leading to the formation and release of vesicles from the plasma membrane and intracellular membrane compartments.…”