Abstract
In this study, we investigated the effects and molecular mechanisms of 2‐phenylbenzimidazole‐5‐sulphonic acid (PBSA), an ultraviolet B protecting agent used in sunscreen lotions and moisturizers, on ovarian cancer cell responses and tumour angiogenesis. PBSA treatment markedly blocked mitogen‐induced invasion through down‐regulation of matrix metalloproteinase (MMP) expression and activity in ovarian cancer SKOV‐3 cells. In addition, PBSA inhibited mitogen‐induced cell proliferation by suppression of cyclin‐dependent kinases (Cdks), but not cyclins, leading to pRb hypophosphorylation and G1 phase cell cycle arrest. These anti‐cancer activities of PBSA in ovarian cancer cell invasion and proliferation were mediated by the inhibition of mitogen‐activated protein kinase kinase 3/6‐p38 mitogen‐activated protein kinase (MKK3/6‐p38MAPK) activity and subsequent down‐regulation of MMP‐2, MMP‐9, Cdk4, Cdk2 and integrin β1, as evidenced by treatment with p38MAPK inhibitor SB203580. Furthermore, PBSA suppressed the expression and secretion of vascular endothelial growth factor in SKOV‐3 cells, leading to inhibition of capillary‐like tubular structures in vitro and angiogenic sprouting ex vivo. Taken together, our results demonstrate the pharmacological effects and molecular targets of PBSA on modulating ovarian cancer cell responses and tumour angiogenesis, and suggest further evaluation and development of PBSA as a promising chemotherapeutic agent for the treatment of ovarian cancer.
Highlights
Ovarian cancer is the second leading cause of mortality among the gynaecologic cancers.[1]
We examined the changes in expression levels and activities of matrix metalloproteinase (MMP), which play important roles in cell invasion, migration, adhesion and proliferation by degrading extracellular matrix (ECM) components and cell surface proteins.[6,7]
It cannot be absolutely excluded that Phenylbenzimidazole-5-sulphonic acid (PBSA)-mediated inhibition of cell invasion is partly mediated by regulation of other MMPs or TIMPs not investigated in this study, these findings suggest that PBSA-mediated down-regulation of MMP expression and proteolytic activity, in particular matrix metalloproteinases-2 (MMP-2) and MMP-9, might inhibit the invasive potential of ovarian cancer cells in response to mitogenic stimulation
Summary
Ovarian cancer is the second leading cause of mortality among the gynaecologic cancers.[1]. | 2689 and integrins mediates aberrant activation of their downstream signalling pathways that triggers uncontrolled and imbalanced responses, suggesting the rational strategy and pharmacological efficacy of RTK/integrin-targeted therapeutics for the treatment of ovarian cancer.[3,4,5] In addition, matrix metalloproteinases (MMPs), which degrade extracellular matrix (ECM) and cellular components in the tissue microenvironment, are closely associated with cancer cell growth and progression as well as normal tissue remodelling.[6,7] High expression and activity of MMPs have been reported to contribute to aggressive phenotypes and poor survival of ovarian cancer.[8,9] inhibition of MMP activity without sufficient knowledge about substrate specificity or physiological roles in cancer biology has been disappointing in various cancer clinical trials.[10] intensive investigations of cellular and molecular networks underlying the progression of ovarian cancer may provide insights into effective therapeutic targets and strategies for the prevention and treatment of cancer. We report the regulatory roles and molecular mechanisms of PBSA in ovarian cancer cell fates including invasion and proliferation, and tumour-derived angiogenic responses
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