hERG1 and CA IX expression are associated with disease recurrence in surgically resected clear cell renal carcinoma

Lastraioli, Elena; Pillozzi, Serena; Mari, Andrea; Tellini, Riccardo; Duranti, Claudia; Bassareo, Valentina; Venturini, Stefano; Minervini, Andrea; Lapini, A.; Nesi, Gabriella; Carini, Marco; Arcangeli, Annarosa

doi:10.1016/j.ejso.2019.10.031

Cited by 13 publications

(11 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3). Finally, the Kv11.1/b1 integrin complex recruits CA-IX, in clear-cell renal carcinoma (ccRC) cells and primary cancer tissues (119). Interestingly, hERG1 and CAIX together represent biomarkers of ccRC progression (119).…”

Section: Continuedmentioning

confidence: 99%

“…Finally, the Kv11.1/b1 integrin complex recruits CA-IX, in clear-cell renal carcinoma (ccRC) cells and primary cancer tissues (119). Interestingly, hERG1 and CAIX together represent biomarkers of ccRC progression (119). In the light of the available information on NHE1 and CAIX physiology, the Kv11.1/b1-integrin/NHE1 and Kv11.1/b1-integrin/CA-IX complexes constitute functional hubs that locally control intraand extracellular pH, especially in hypoxic conditions, which drive progression-prone, prometastatic signaling pathways.…”

Section: Continuedmentioning

confidence: 99%

See 1 more Smart Citation

Dynamics and physiological meaning of complexes between ion channels and integrin receptors: the case of Kv11.1

Becchetti

Duranti

Arcangeli

2022

American Journal of Physiology-Cell Physiology

View full text Add to dashboard Cite

The cellular functions are regulated by a complex interplay of diffuse and local signals. Experimental work in cell physiology has led to recognize that understanding a cell's dynamics requires a deep comprehension of local fluctuations of cytosolic regulators. Macromolecular complexes are major determinants of local signaling. Multi-enzyme assemblies limit the diffusion restriction to reaction kinetics by direct exchange of metabolites. Likewise, close coupling of ion channels and transporters modulate the ion concentration around a channel mouth or transporter binding site. Extreme signal locality is brought about by conformational coupling between membrane proteins, as is typical of mechanotransduction. A paradigmatic case is integrin-mediated cell adhesion. Sensing the extracellular microenvironment and providing an appropriate response is essential in growth and development and has innumerable pathological implications. The process involves bidirectional signal transduction by complex supra-molecular structures that link integrin receptors to ion channels and transporters, growth factor receptors, cytoskeletal elements and other regulatory elements. The dynamics of such complexes is only beginning to be understood. A thoroughly studied example is the association between integrin receptors and the voltage-gated K+ channels Kv11.1. These channels are widely expressed in early embryos, where their physiological roles are poorly understood and apparently different from the shaping of action potential firing in the adult. Hints about these roles come from studies in cancer cells, where Kv11.1 is often overexpressed and appears to re-assume functions, such as controlling cell proliferation/differentiation, apoptosis and migration. Kv11.1 is implicated in these processes through its linking to integrin subunits.

show abstract

Section: Continuedmentioning

confidence: 99%

Section: Continuedmentioning

confidence: 99%

Dynamics and physiological meaning of complexes between ion channels and integrin receptors: the case of Kv11.1

Becchetti

Duranti

Arcangeli

2022

American Journal of Physiology-Cell Physiology

View full text Add to dashboard Cite

show abstract

“…Interestingly, VGSCs may not be the only type of ion channel related to oncological surgery. Retrospective univariate and multivariate analyses showed that hERG1 expression had a significant negative association with disease recurrence in surgically resected clear cell renal carcinoma [ 20 ].…”

Section: Therapeutic Modalitiesmentioning

confidence: 99%

Combinatorial Therapy of Cancer: Possible Advantages of Involving Modulators of Ionic Mechanisms

Djamgoz

2022

Cancers

View full text Add to dashboard Cite

Cancer is a global health problem that 1 in 2–3 people can expect to experience during their lifetime. Several different modalities exist for cancer management, but all of these suffer from significant shortcomings in both diagnosis and therapy. Apart from developing completely new therapies, a viable way forward is to improve the efficacy of the existing modalities. One way is to combine these with each other or with other complementary approaches. An emerging latter approach is derived from ionic mechanisms, mainly ion channels and exchangers. We evaluate the evidence for this systematically for the main treatment methods: surgery, chemotherapy, radiotherapy and targeted therapies (including monoclonal antibodies, steroid hormones, tyrosine kinase inhibitors and immunotherapy). In surgery, the possible systemic use of local anesthetics to suppress subsequent relapse is still being discussed. For all the other methods, there is significant positive evidence for several cancers and a range of modulators of ionic mechanisms. This applies also to some of the undesirable side effects of the treatments. In chemotherapy, for example, there is evidence for co-treatment with modulators of the potassium channel (Kv11.1), pH regulation (sodium–hydrogen exchanger) and Na+-K+-ATPase (digoxin). Voltage-gated sodium channels, shown previously to promote metastasis, appear to be particularly useful for co-targeting with inhibitors of tyrosine kinases, especially epidermal growth factor. It is concluded that combining current orthodox treatment modalities with modulators of ionic mechanisms can produce beneficial effects including (i) making the treatment more effective, e.g., by lowering doses; (ii) avoiding the onset of resistance to therapy; (iii) reducing undesirable side effects. However, in many cases, prospective clinical trials are needed to put the findings firmly into clinical context.

show abstract

“…Among them, potassium channels exert a key role [ 7 ]. In particular, the human ether-á-go-go–related gene (hERG1) is expressed in different types of human solid cancers, while absent in normal tissues [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. In fact, hERG1 is physiologically expressed in excitable tissues, particularly in the heart where it regulates the repolarization phase of the cardiac action potential [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

“…This occurs through the formation of a molecular complex with the β1 subunit of the integrin receptors [ 24 ]. Overall, hERG1 could represent a novel cancer biomarker and a therapeutic target in different tumours [ 16 , 25 , 26 , 27 , 28 , 29 ]. However, the strong physiological expression of hERG1 in the human cardiomyocytes limits if not eliminates the possibility of targeting the channel as it is [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

Combination Therapy with a Bispecific Antibody Targeting the hERG1/β1 Integrin Complex and Gemcitabine in Pancreatic Ductal Adenocarcinoma

Lottini

Duranti

Iorio

et al. 2023

Cancers

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDAC) represents an unmet medical need. Difficult/late diagnosis as well as the poor efficacy and high toxicity of chemotherapeutic drugs result in dismal prognosis. With the aim of improving the treatment outcome of PDAC, we tested the effect of combining Gemcitabine with a novel single chain bispecific antibody (scDb) targeting the cancer-specific hERG1/β1 integrin complex. First, using the scDb (scDb-hERG1-β1) in immunohistochemistry (IHC), Western blot (WB) analysis and immunofluorescence (IF), we confirmed the presence of the hERG1/β1 integrin complex in primary PDAC samples and PDAC cell lines. Combining Gemcitabine with scDb-hERG1-β1 improved its cytotoxicity on all PDAC cells tested in vitro. We also tested the combination treatment in vivo, using an orthotopic xenograft mouse model involving ultrasound-guided injection of PDAC cells. We first demonstrated good penetration of the scDb-hERG1-β1 conjugated with indocyanine green (ICG) into tumour masses by photoacoustic (PA) imaging. Next, we tested the effects of the combination at either therapeutic or sub-optimal doses of Gemcitabine (25 or 5 mg/kg, respectively). The combination of scDb-hERG1-β1 and sub-optimal doses of Gemcitabine reduced the tumour masses to the same extent as the therapeutic doses of Gemcitabine administrated alone; yielded increased survival; and was accompanied by minimised side effects (toxicity). These data pave the way for a novel therapeutic approach to PDAC, based on the combination of low doses of a chemotherapeutic drug (to minimize adverse side effects and the onset of resistance) and the novel scDb-hERG1-β1 targeting the hERG1/β1 integrin complex as neoantigen.

show abstract

hERG1 and CA IX expression are associated with disease recurrence in surgically resected clear cell renal carcinoma

Cited by 13 publications

References 28 publications

Dynamics and physiological meaning of complexes between ion channels and integrin receptors: the case of Kv11.1

Dynamics and physiological meaning of complexes between ion channels and integrin receptors: the case of Kv11.1

Combinatorial Therapy of Cancer: Possible Advantages of Involving Modulators of Ionic Mechanisms

Combination Therapy with a Bispecific Antibody Targeting the hERG1/β1 Integrin Complex and Gemcitabine in Pancreatic Ductal Adenocarcinoma

Contact Info

Product

Resources

About