The Potential for Connexin Hemichannels to Drive Breast Cancer Progression through Regulation of the Inflammatory Response

Rhett, J. Matthew; Yeh, Elizabeth S.

doi:10.3390/ijms19041043

Cited by 15 publications

(13 citation statements)

References 129 publications

(164 reference statements)

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“…[3][4][5] Many causes of BC,such as angiogenesis,immunotolerance,invasiveness,metastasis,and resistance,a re associated with inflammation. [6] Moreover, multiple hyper-activated signaling pathways and activation of macrophages in tumor microenvironment are also involved in the metastasis of BC. [7,8] Cyclooxygenase (COX) is ac rucial enzyme responsible for the conversion of arachidonic acid into various prostanoids.A sa ni soform of COX family,C OX-2 is undetectable in normal tissues but is overexpressed in BC with elevated prostaglandin E2 (PGE2), which affects the migration of BC cells, [9] and marks apoor prognosis of BC.…”

Section: Introductionmentioning

confidence: 99%

Multispecific Platinum(IV) Complex Deters Breast Cancer via Interposing Inflammation and Immunosuppression as an Inhibitor of COX‐2 and PD‐L1

et al. 2020

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Breast cancer (BC) is one of the most common malignancies in women and often accompanied by inflammatory processes.Cyclooxygenase-2 (COX-2) playsavital role in the progression of BC,c orrelating with the expression of programmed death-ligand 1(PD-L1). Overexpression of PD-L1 contributes to the immune escape of cancer cells,a nd its blockade would stimulate anticancer immunity.T wo multispecific platinum(IV) complexes DNP and NP were prepared using non-steroidal antiinflammatory drug naproxen (NPX) as axial ligand(s) to inhibit the BC cells.D NP exhibited high cytotoxicity and antiinflammatory properties superior over NP, cisplatin and NPX;m oreover,i td isplayed potent antitumor activity and almost no general toxicity in mice bearing triplenegative breast cancer (TNBC). Mechanistic studies revealed that DNP could downregulate the expression of COX-2 and PD-L1 in vitro and vivo,inhibit the secretion of prostaglandin, reduce the expression of BC-associated protein BRD4 and phosphorylation of extracellular signal-regulated kinases 1/2 (Erk1/2), and block the oncogene c-Myc in BC cells.T hese findings demonstrate that DNP is capable of intervening in inflammatory,i mmune,a nd metastatic processes of BC,t hus presenting anew mechanism of action for anticancer platinum-(IV) complexes.T he multispecificity offers as pecial superiority for DNP to treat TNBC by combining chemotherapyand immunotherapyi none molecule.

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Section: Introductionmentioning

confidence: 99%

Multispecific Platinum(IV) Complex Deters Breast Cancer via Interposing Inflammation and Immunosuppression as an Inhibitor of COX‐2 and PD‐L1

et al. 2020

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“…However, there has also been a documented role for connexin hemichannels in promoting inflammation (reviewed in [ 234 ]), potentially through the release of ATP to activate cytokine release by macrophages. Connexin mimetic peptides that block hemichannel function, including aCT1 and JM2, decrease inflammation during wound healing [ 235 , 236 ] and in response to CNS injuries [ 237 , 238 ].…”

Section: Mechanistic Roles Of Connexins In More Recently Appreciatmentioning

confidence: 99%

Connexins in Cancer: Jekyll or Hyde?

2020

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The expression, localization, and function of connexins, the protein subunits that comprise gap junctions, are often altered in cancer. In addition to cell–cell coupling through gap junction channels, connexins also form hemichannels that allow communication between the cell and the extracellular space and perform non-junctional intracellular activities. Historically, connexins have been considered tumor suppressors; however, they can also serve tumor-promoting functions in some contexts. Here, we review the literature surrounding connexins in cancer cells in terms of specific connexin functions and propose that connexins function upstream of most, if not all, of the hallmarks of cancer. The development of advanced connexin targeting approaches remains an opportunity for the field to further interrogate the role of connexins in cancer phenotypes, particularly through the use of in vivo models. More specific modulators of connexin function will both help elucidate the functions of connexins in cancer and advance connexin-specific therapies in the clinic.

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“…More recently, a role for extracellular nucleotides and paracrine signalling in organ fibrosis has been highlighted (Becker et al., ; Dosch et al., ; Hills et al., ). Not surprisingly, strict control of connexin activity is imperative in maintaining cellular function and is further supported by the observation that there are a large number of diseases in which mutations and/or single nucleotide polymorphisms result in inflammation (Rhett & Yeh, ; Tsuchida et al., ), ischaemia (Sahu & Bera, ) and essential (Gal et al., ) or renin‐induced hypertension (Firouzi et al., ). Consequently, hemi‐channel gating is regulated in response to various stimuli including changes in cell proliferation and intracellular calcium, increased apoptosis, post‐translational modification, and changes in pH and cell volume (reviewed in Bosco et al., ).…”

Section: Introductionmentioning

confidence: 95%

Connexin‐mediated cell communication in the kidney: A potential therapeutic target for future intervention of diabetic kidney disease?

Price

Potter

Williams

et al. 2020

Experimental Physiology

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The ability of cells to communicate and synchronise their activity is essential for the maintenance of tissue structure, integrity and function. A family of membrane-bound proteins called connexins are largely responsible for mediating the local transfer of information between cells. Assembled in the cell membrane as a hexameric connexon, they either function as a conduit for paracrine signalling, forming a transmembrane hemi-channel, or, if aligned with connexons on neighbouring cells, form a continuous aqueous pore or gap junction, which allows for the direct transmission of metabolic and electrical signals. Regulation of connexin synthesis and activity is critical to cellular function, and a number of diseases are attributed to changes in the expression and/or function of these important proteins. A link between hyperglycaemia, connexin expression, altered nucleotide concentrations and impaired function highlights a potential role for connexin-mediated cell communication in complications of diabetes. In the diabetic kidney, glycaemic injury is the leading cause of end-stage renal failure, reflecting multiple aetiologies including glomerular hyperfiltration, albuminuria, increased deposition of extracellular matrix and tubulointerstitial fibrosis.Loss of connexin-mediated cell-to-cell communication in diabetic nephropathy may represent an early sign of disease progression, but our understanding of the process remains severely limited. This review focuses on recent evidence demonstrating that glucose-evoked changes in connexin-mediated cell communication and associated purinergic signalling may contribute to the pathogenesis of kidney disease in diabetes, highlighting the tantalising potential of targeting these proteins as a novel therapeutic intervention.

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The Potential for Connexin Hemichannels to Drive Breast Cancer Progression through Regulation of the Inflammatory Response

Cited by 15 publications

References 129 publications

Multispecific Platinum(IV) Complex Deters Breast Cancer via Interposing Inflammation and Immunosuppression as an Inhibitor of COX‐2 and PD‐L1

Multispecific Platinum(IV) Complex Deters Breast Cancer via Interposing Inflammation and Immunosuppression as an Inhibitor of COX‐2 and PD‐L1

Connexins in Cancer: Jekyll or Hyde?

Connexin‐mediated cell communication in the kidney: A potential therapeutic target for future intervention of diabetic kidney disease?

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