The human ion channel TRPM2 modulates migration and invasion in neuroblastoma through regulation of integrin expression

Bao, Lei; Festa, Fernanda; Hirschler-Laszkiewicz, Iwona; Keefer, Kerry; Wang, Honggang; Cheung, Joseph Y.; Miller, Barbara A.

doi:10.1038/s41598-022-25138-w

Cited by 5 publications

(2 citation statements)

References 90 publications

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“…Inhibition of integrin α 1 β 1 reduced tumor cell invasion in the ECM in chemotherapy-treated mice. Treatment with obtustatin, a KTS disintegrin, a specific inhibitor of α 1 β 1 , reduced the movement of triple-negative breast cancer cells inoculated on a V-type collagen matrix [ 20 ] and reduced the migration and invasion of neuroblastoma cells with high TRPM2 expression [ 21 ], indicating the potential of α 1 β 1 to increase cancer cell metastasis. These findings suggest that integrin α 1 β 1 is an important target for intervention in cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

Integrin Targeting Enhances the Antimelanoma Effect of Annexin V in Mice

Zhu

Gao

et al. 2023

IJMS

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Malignant melanoma, an increasingly common form of skin cancer, is a major threat to public health, especially when the disease progresses past skin lesions to the stage of advanced metastasis. Targeted drug development is an effective strategy for the treatment of malignant melanoma. In this work, a new antimelanoma tumor peptide, the lebestatin–annexin V (designated LbtA5) fusion protein, was developed and synthesized by recombinant DNA techniques. As a control, annexin V (designated ANV) was also synthesized by the same method. The fusion protein combines annexin V, which specifically recognizes and binds phosphatidylserine, with the disintegrin lebestatin (lbt), a polypeptide that specifically recognizes and binds integrin α1β1. LbtA5 was successfully prepared with good stability and high purity while retaining the dual biological activity of ANV and lbt. MTT assays demonstrated that both ANV and LbtA5 could reduce the viability of melanoma B16F10 cells, but the activity of the fusion protein LbtA5 was superior to that of ANV. The tumor volume growth was slowed in a mouse xenograft model treated with ANV and LbtA5, and the inhibitory effect of high concentrations of LbtA5 was significantly better than that of the same dose of ANV and was comparable to that of DTIC, a drug used clinically for melanoma treatment. The hematoxylin and eosin (H&E) staining test showed that ANV and LbtA5 had antitumor effects, but LbtA5 showed a stronger ability to induce melanoma necrosis in mice. Immunohistochemical experiments further showed that ANV and LbtA5 may inhibit tumor growth by inhibiting angiogenesis in tumor tissue. Fluorescence labeling experiments showed that the fusion of ANV with lbt enhanced the targeting of LbtA5 to mouse melanoma tumor tissue, and the amount of target protein in tumor tissue was significantly increased. In conclusion, effective coupling of the integrin α1β1-specific recognition molecule lbt confers stronger biological antimelanoma effects of ANV, which may be achieved by the dual effects of effective inhibition of B16F10 melanoma cell viability and inhibition of tumor tissue angiogenesis. The present study describes a new potential strategy for the application of the promising recombinant fusion protein LbtA5 in the treatment of various cancers, including malignant melanoma.

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Section: Discussionmentioning

confidence: 99%

Integrin Targeting Enhances the Antimelanoma Effect of Annexin V in Mice

Zhu

Gao

et al. 2023

IJMS

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“…In neuroblastoma, the same pathway is activated by TRPM2, along with the transcription factors HIF-1α1, E2F1, FOXM1, and CREB. Activation of TRPM2 increased the expression of α1, αv, β1, and β5 integrins and, consecutively, migration and invasion of neuroblastoma [89].…”

Section: Trp Channels Modulation By Oxidative Stress In Cancer Cell M...mentioning

confidence: 91%

TRP Channels in Tumoral Processes Mediated by Oxidative Stress and Inflammation

Piciu,

Balas,

Badea

et al. 2023

Antioxidants

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The channels from the superfamily of transient receptor potential (TRP) activated by reactive oxygen species (ROS) can be defined as redox channels. Those with the best exposure of the cysteine residues and, hence, the most sensitive to oxidative stress are TRPC4, TRPC5, TRPV1, TRPV4, and TRPA1, while others, such as TRPC3, TRPM2, and TRPM7, are indirectly activated by ROS. Furthermore, activation by ROS has different effects on the tumorigenic process: some TRP channels may, upon activation, stimulate proliferation, apoptosis, or migration of cancer cells, while others inhibit these processes, depending on the cancer type, tumoral microenvironment, and, finally, on the methods used for evaluation. Therefore, using these polymodal proteins as therapeutic targets is still an unmet need, despite their draggability and modulation by simple and mostly unharmful compounds. This review intended to create some cellular models of the interaction between oxidative stress, TRP channels, and inflammation. Although somewhat crosstalk between the three actors was rather theoretical, we intended to gather the recently published data and proposed pathways of cancer inhibition using modulators of TRP proteins, hoping that the experimental data corroborated clinical information may finally bring the results from the bench to the bedside.

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Integrin‐α5 expression and its role in non‐small cell lung cancer progression

Ka,

Matsumoto,

Ando

et al. 2024

Cancer Science

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Integrins are transmembrane receptors that facilitate cell adhesion to the extracellular matrix and neighboring cells. Aberrant expression of integrins has been associated with tumor progression and metastasis in various cancer types. Integrin alpha‐5 (ITGA5) is an integrin subtype that serves as a receptor for fibronectin, fibrinogen, and fibrillin‐1. The purpose of this study was to elucidate how ITGA5 expression plays a role in human non‐small cell lung cancer (NSCLC). Our clinical data, along with data retrieved from The Cancer Genome Database (TCGA), revealed that high ITGA5 expression in NSCLC patients was associated with a lower recurrence‐free survival and overall survival. In our in vitro functional assays, ITGA5 overexpression in human NSCLC cell lines resulted in increased cell size, adhesion, and migration properties, while knockdown of ITGA5 restored the phenotypes. Correspondingly, knockdown and inhibition of ITGA5 in endogenously high‐expressing NSCLC cell lines resulted in decreased cell size, adhesion, migration, and proliferation. The antiproliferative effect was also confirmed by a reduction in Ki‐67 without discernible changes in apoptosis. Collectively, these findings reveal the significant role of ITGA5 in various functional behaviors in NSCLC, providing a potential therapeutic target for NSCLC patients with high ITGA5 expression.

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The human ion channel TRPM2 modulates migration and invasion in neuroblastoma through regulation of integrin expression

Cited by 5 publications

References 90 publications

Integrin Targeting Enhances the Antimelanoma Effect of Annexin V in Mice

Integrin Targeting Enhances the Antimelanoma Effect of Annexin V in Mice

TRP Channels in Tumoral Processes Mediated by Oxidative Stress and Inflammation

Integrin‐α5 expression and its role in non‐small cell lung cancer progression

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