Therapeutic targeting of anoikis resistance in cutaneous melanoma metastasis

Neuendorf, Hannah M.; Simmons, Jacinta L.; Boyle, Glen M.

doi:10.3389/fcell.2023.1183328

Cited by 10 publications

(3 citation statements)

References 357 publications

(386 reference statements)

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“…In the course of metastasis, malignant cells dissociate from their primary site and migrate to give rise to metastatic tumors at distant sites. The sensitization of non-adhered cells to cell death, such as anoikis, is recently regarded as an effective therapeutic strategy for metastasis [56,57]. This study demonstrated that GO preferentially exerts its detrimental effects on non-adhered cells.…”

Section: Discussionmentioning

confidence: 71%

Adhesion States Greatly Affect Cellular Susceptibility to Graphene Oxide: Therapeutic Implications for Cancer Metastasis

Morotomi-Yano,

Hayami,

Yano

2024

IJMS

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Graphene oxide (GO) has received increasing attention in the life sciences because of its potential for various applications. Although GO is generally considered biocompatible, it can negatively impact cell physiology under some circumstances. Here, we demonstrate that the cytotoxicity of GO greatly varies depending on the cell adhesion states. Human HCT-116 cells in a non-adhered state were more susceptible to GO than those in an adherent state. Apoptosis was partially induced by GO in both adhered and non-adhered cells to a similar extent, suggesting that apoptosis induction does not account for the selective effects of GO on non-adhered cells. GO treatment rapidly decreased intracellular ATP levels in non-adhered cells but not in adhered ones, suggesting ATP depletion as the primary cause of GO-induced cell death. Concurrently, autophagy induction, a cellular response for energy homeostasis, was more evident in non-adhered cells than in adhered cells. Collectively, our observations provide novel insights into GO’s action with regard to cell adhesion states. Because the elimination of non-adhered cells is important in preventing cancer metastasis, the selective detrimental effects of GO on non-adhered cells suggest its therapeutic potential for use in cancer metastasis.

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Section: Discussionmentioning

confidence: 71%

Adhesion States Greatly Affect Cellular Susceptibility to Graphene Oxide: Therapeutic Implications for Cancer Metastasis

Morotomi-Yano,

Hayami,

Yano

2024

IJMS

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“…Although anoikis has long been recognized as an important cellular process, there is a limited understanding of its regulation, and a great need for therapeutics that specifically induce it. [72, 73, 80, 81] Findings from the current study provide a new means to specifically target anoikis. Further, the small chemical nature of Dxr2-017 also represents a new tool that can be used as a probe to interrogate biology.…”

Section: Discussionmentioning

confidence: 93%

Protein Structure Inspired Drug Discovery

Qiao,

Binknowski,

Broughan

et al. 2024

Preprint

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Drug discovery starts with known function, either of a compound or a protein, in-turn prompting investigations to probe 3D structure of the compound-protein interface. As protein structure determines function, we hypothesized that unique 3D structural motifs represent primary information denoting unique function that can drive discovery of novel agents. Using a physics-based protein structure analysis platform developed by us, designed to conduct computationally intensive analysis at supercomputing speeds, we probed a high-resolution protein x-ray crystallographic library developed by us. We selected 3D structural motifs whose function was not otherwise established, that offered environments supporting binding of drug-like chemicals and were present on proteins that were not established therapeutic targets. For each of eight potential binding pockets on six different proteins we accessed a 60 million compound library and used our analysis platform to evaluate binding. Using eight-day colony formation assays acquired compounds were screened for efficacy against human breast, prostate, colon and lung cancer cells and toxicity against human bone marrow stem cells. Compounds selectively inhibiting cancer growth segregated to two pockets on separate proteins. The compound, Dxr2-017, exhibited selective activity against human melanoma cells in the NCI-60 cell line screen, had an IC50 of 19 nM against human melanoma M14 cells in our eight-day assay, while over 2100-fold higher concentrations inhibited stem cells by less than 30%. We show that Dxr2-017 induces anoikis, a unique form of programmed cell death in need of targeted therapeutics. The predicted target protein for Dxr2-017 is expressed in bacteria, not in humans. This supports our strategy of focusing on unique 3D structural motifs. It is known that functionally important 3D structures are evolutionarily conserved. Here we demonstrate proof-of-concept that protein structure represents high value primary data to support discovery of novel therapeutics. This approach is widely applicable.

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“…Considering our experimental results and the current increasing availability of combined immunotherapy for CM, the feasibility of individualized treatment for patients has likewise increased, which may be beneficial for highly aggressive, highly refractory, advanced, and metastatic CM. In fact, given the important role of anoikis in early metastasis of CM, there are several ongoing CM clinical trials targeting anoikis resistance [ 45 ]. However, the unsatisfactory response rate in CM patients warrants further investigation into the causes of the differences.…”

Section: Discussionmentioning

confidence: 99%

Development of anoikis-related long non-coding RNA signature associated with prognosis and immune landscape in cutaneous melanoma patients

Zhong

Qian

Gong

et al. 2023

Aging

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Background: Anoikis is involved in many critical biological processes in tumors; however, function in CM is still unknown. In this study, the relevance between Anoikis-related lncRNAs (ARLs) and the clinicopathological characteristics of patients with CM was comprehensively assessed. Methods: Through analysis of TCGA dataset, ARLs were identified by using TCGA dataset. Based on the ARLs, a risk model was established to anticipate the prognosis of patients with CM, besides, the prediction accuracy of the model was evaluated. The immune infiltration landscape of patients with CM was assessed comprehensively, and the correlation between ARLs and immunity was elucidated. Immunotherapy and drug sensitivity analyses were applied to analyze the treatment response in patients with CM with diverse risk scores. Different subgroups were distinguished among the patients using consensus cluster analysis. Results: A risk model based on six ARLs was set up to obtain an accurate prediction of the prognosis of patients with CM. There were distinctions in the immune landscape among CM patients with diverse risk scores and subgroups. Six prognosis-related ARLs were highly correlated with the number of immune cells. Patients with CM with different risk scores have various sensitivities to immunotherapy and antitumor drug treatments. Conclusion: Our newly risk model associated with ARLs has considerable prognostic value for patients with CM. Not only has the risk model high prediction accuracy but it also indicates the immune status of CM patients, which will provide a new direction for the individualized therapy of patients with CM.

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Therapeutic targeting of anoikis resistance in cutaneous melanoma metastasis

Cited by 10 publications

References 357 publications

Adhesion States Greatly Affect Cellular Susceptibility to Graphene Oxide: Therapeutic Implications for Cancer Metastasis

Adhesion States Greatly Affect Cellular Susceptibility to Graphene Oxide: Therapeutic Implications for Cancer Metastasis

Protein Structure Inspired Drug Discovery

Development of anoikis-related long non-coding RNA signature associated with prognosis and immune landscape in cutaneous melanoma patients

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