Abstract
Purpose: Calcium-sensing receptor (CaSR) has been associated with breast cancer metastasis tothe bone. Targeting chemoattractant factors, such as calcium, that are released in response tobone resorption could prevent metastasis and induce apoptosis of cancer cells. In the presentstudy, we investigated the potential caspase 3/7 activation following treatment with a CaSRantagonist, NPS-2143, in breast cancer cells. In addition, the effects of NPS-2143 on breastcancer cell proliferation, migration and invasion were assessed. Methods: Colorimetric MTT assay was used to evaluate cell viability. Apo-one homogeneouscaspase-3/7 assay was used to measure caspase 3/7 activities in breast cancer cells. Cellmigration and invasion were assessed using scratch wound assay and matrigel invasionchambers, respectively. The protein expressions of p-ERK1/2, integrin β1 and Bcl-2 wereevaluated using western blotting. Results: Our study revealed that NPS-2143 significantly reduced cell proliferation with halfmaximal (50%) inhibitory concentration (IC50) values of 4.08 and 5.71 μM in MDA-MB-231 and MCF-7 cells, respectively. NPS-2143 induced caspase 3/7 activation in MDA-MB-231 breastcancer cells which was accompanied with a remarkable reduction in the expression of Bcl-2antiapoptotic protein. NPS-2143 suppressed migratory and invasive abilities of MDA-MB-231cells with a significant reduction in the expression of p-ERK1/2 and integrin β1 proteins. Conclusion: Our study confirms the ability NPS-2143 to suppress proliferative, migratory andinvasive effects of breast cancer cells which was accompanied by caspase 3/7 activation andsuggests the potential of NPS-2143 as a promising anti-cancer molecule in breast cancer.
Highlights
Introduction ipBreast cancer, the most common type of cancer in women, commonly metastasizes to the bone.[1,2] During bone resorption, several chemoattractant factors are released and they are r considered the main driver of such selective metastatic destination to the bone.[1,3] characterizing molecular targets underlying this highly metastatic disease may lead to better c therapeutics and improve such poor outcome
We found that NPS-2143 treatment had significant anticancer effects on breast cancer cells which was represented by suppression of cell proliferation and stimulation of caspase-dependent apoptosis
M cancer such as p-ERK1/2, integrin β1 and B-cell lymphoma 2 (Bcl-2), which are all often altered in breast cancer
Summary
Introduction ipBreast cancer, the most common type of cancer in women, commonly metastasizes to the bone.[1,2] During bone resorption, several chemoattractant factors are released and they are r considered the main driver of such selective metastatic destination to the bone.[1,3] characterizing molecular targets underlying this highly metastatic disease may lead to better c therapeutics and improve such poor outcome. 231 cells which has higher expression levels compared to nonmalignant breast cell lines.[4,5,6,7] u The CaSR is a class C/ G protein–coupled receptor that has a well-established physiologic role in regulating extracellular calcium levels and parathyroid hormone (PTH) release.[8] There is an increasing evidence from recent studies supporting the association of aberrant n CaSR signaling in the growth and metastasis of several human cancers such as ovary, breast, kidney and prostate cancer.[8,9] For instance, overexpression of a functional CaSR amplifies a the osteolytic ability of metastatic breast cancer cells.[10] In addition, small interfering RNA (siRNA) targeting CaSR could inhibit cell migration and proliferation in response to high Ca2+ concentration in breast cancer cell lines.[1,11] stimulation of CaSR could
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