Dynamin 2 Inhibitors as Novel Therapeutic Agents Against Cervical Cancer Cells

Lee, Yoo-Young; Jeon, Hye-Kyung; Lee, Jung-Eun; Hong, Juhee; Do, In‐Gu; Choi, Chel Hun; Kim, Tae-Joong; Kim, Byoung-Gie; Bae, Duk-Soo; Kim, Yong-Chul; Lee, Jeong‐Won

doi:10.21873/anticanres.11235

Cited by 14 publications

(13 citation statements)

References 18 publications

(26 reference statements)

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“…Interactions with signaling molecules provide a major focus for disrupted signaling. Cav-1, being a key protein of the caveolae, is critical for cancer development, as it directly interacts with signaling proteins, including phosphoinositide 3-kinase, Src, phospholipases, extracellular signal-regulated kinase, G-proteins, endothelial nitric oxide synthase, adenylyl cyclase, protein kinase C, p53 and cell division control protein 42 homolog, and is involved in signal transduction cascades (13,58,59). Dysfunction of Cav-1, resulting from the aberrant expression of the gene, triggers the activation of various growth-promoting pathways (4,11).…”

Section: Discussionmentioning

confidence: 99%

Caveolin‑1 and dynamin‑2 overexpression is associated with the progression of bladder cancer

et al. 2019

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Caveolae-mediated endocytosis regulates cell adhesion and growth in an anchorage-dependent manner. Studies of the endocytic function of caveolae have suggested a wide-ranging list of cargoes, including a number of receptors and extracellular proteins, ligands and nutrients from the extracellular matrix. Disruption of the processes of caveolae-mediated endocytosis mediated by signaling proteins is critical to cellular integrity. Caveolin-1 and dynamin-2 are the 2 major proteins associated with endocytotic function. Mechanistically, dynamin-2 has a co-equal role with caveolin-1 in terms of caveolae-derived endosome formation. Recent studies have revealed the pathological outcomes associated with the dysregulation of caveolin-1 and dynamin-2 expression. Increased expression levels of the gene for caveolin, Cav-1, resulting in augmented cellular metastasis and invasion, have been demonstrated in various types of cancer, and overexpression of the gene for dynamin-2, DNM2, has been associated with tumorigenesis in cervical, pancreatic and lung cancer. An increased expression of Cav-1 and DNM2 is known to be associated with the invasive behavior of cancer cells, and with cancer progression. Furthermore, it has been previously demonstrated that, in caveolar assembly and caveolae mediated endocytosis, Cav-1 interacts directly with DNM2 during the processes. Altered expression of the 2 genes is critical for the normal function of the cell. The expression patterns of Cav-1 and DNM2 have been previously examined in bladder cancer cell lines, and were each demonstrated to be overexpressed. In the present study, the expression levels of these 2 genes in bladder cancer samples were quantified. The gene expression levels of Cav-1 and DNM2 were identified to be increased 8.88-and 8.62-fold, respectively, in tumors compared with the normal controls. Furthermore, high-grade tumors exhibited significantly increased expression levels of Cav-1 and DNM2 (both P<0.0001) compared with the low-grade tumors. In addition, compared with normal control samples, the expression of the 2 genes in tumor samples was observed to be highly significant (P<0.0001), with a marked positive correlation identified for the tumors (Pearson's correlation coefficient, r=0.80 for the tumor samples vs. r=0.32 in the normal control samples). Taken together, the results of the present study demonstrated that the overexpression of Cav-1 and DNM2 genes, and a determination of their correlation coefficients, may be a potential risk factor for bladder cancer, in addition to other clinical factors.

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Section: Discussionmentioning

confidence: 99%

Caveolin‑1 and dynamin‑2 overexpression is associated with the progression of bladder cancer

et al. 2019

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“…In preclinical models, dynamin 2 gene silencing significantly reduced cell migration and invasion in vitro , as well as tumor size and lymph node metastases in vivo [39]. Level of dynamin 2 was also found to be increased in the cervical cancer, which might be related to the increased proliferation, dysfunction of apoptotic activity and increased migration [40]. Together these results suggest that both enzymatic activity and proper localization of dynamin 2 are required for extracellular matrix degradation by invasive cancer cells [41].…”

Section: Therapeutic Potential Of Dynamin Isoformsmentioning

confidence: 99%

Distinct functions of dynamin isoforms in tumorigenesis and their potential as therapeutic targets in cancer

Meng

2017

Oncotarget

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Dynamins and their related proteins participate in the regulation of neurotransmission, antigen presentation, receptor internalization, growth factor signalling, nutrient uptake, and pathogen infection. Recently, emerging findings have shown dynamin proteins can also contribute to the genesis of cancer. This up-to-date review herein focuses on the functionality of dynamin in cancer development. Dynamin 1 and 2 both enhance cancer cell proliferation, tumor invasion and metastasis, whereas dynamin 3 has tumor suppression role. Antisense RNAs encoded on the DNA strand opposite a dynamin gene regulate the function of dynamin, and manipulate oncogenes and tumor suppressor genes. Certain dynamin-related proteins are also upregulated in distinct cancer conditions, resulting in apoptotic resistance, cell migration and poor prognosis. Altogether, dynamins are potential biomarkers as well as representing promising novel therapeutic targets for cancer treatment. This study also summarizes the current available dynamin-targeted therapeutics and suggests the potential strategy based on signalling pathways involved, providing important information to aid the future development of novel cancer therapeutics by targeting these dynamin family members.

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“…Interestingly, nontumorigenic fibroblasts treated with DNM2 inhibitors appear less sensitive to cell death than cancer cells [76,77]. A benefit a DNM2 inhibition to reduce cell proliferation and/or induce apoptosis was confirmed in a wide range of cancer cells including cervical epithelial cancer cells [80], prostate cancer cells [36,42], non-small-cell lung cancer cells [81], glioblastoma cells [82], chronic myeloid leukemia cells [32], B-and T-ALL cells [31] and hepatocellular carcinoma cells [83]. The similar benefit using pharmacological DNM2 inhibitors [74,75,82,[84][85][86][87][88] or DNM2 gene silencing demonstrates the requirement of the DNM2 GTPase activity in the phenotypes occurring in these cancer cells.…”

Section: Therapeutic Developmentsmentioning

confidence: 92%

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

Trochet

Bitoun

2021

J Exp Clin Cancer Res

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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.

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Dynamin 2 Inhibitors as Novel Therapeutic Agents Against Cervical Cancer Cells

Abstract: Targeting dynamin 2 may be a promising new approach for the treatment of cervical cancer.

Cited by 14 publications

References 18 publications

Caveolin‑1 and dynamin‑2 overexpression is associated with the progression of bladder cancer

Caveolin‑1 and dynamin‑2 overexpression is associated with the progression of bladder cancer

Distinct functions of dynamin isoforms in tumorigenesis and their potential as therapeutic targets in cancer

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

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