Inositol 1, 4, 5-trisphosphate-dependent nuclear calcium signals regulate angiogenesis and cell motility in triple negative breast cancer.

Erika Guimarães,Andressa França,André Oliveira,Carlos Gonçalves,Luciana Drumond,José Miguel Ortega,Clarissa Carvalho,M Fátima Leite,Brígida Almeida,Marina De Brot,Ana Cândida Araújo E Silva,Gabriel Fernandes,Puebla Cassini,Rodrigo Machado,Bárbara Hissa,Márcio Moraes,Matheus De Castro Fonseca,Lucíola Barcelos,Ruby John Anto

doi:10.1371/journal.pone.0175041

Erika Guimarães, Andressa França + Show 17 more

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https://doi.org/10.1371/journal.pone.0175041

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Abstract

Increases in nuclear calcium concentration generate specific biological outcomes that differ from those resulting from increased cytoplasmic calcium. Nuclear calcium effects on tumor cell proliferation are widely appreciated; nevertheless, its involvement in other steps of tumor progression is not well understood. Therefore, we evaluated whether nuclear calcium is essential in other additional stages of tumor progression, including key steps associated with the formation of the primary tumor or with the metastatic cascade. We found that nuclear calcium buffering impaired 4T1 triple negative breast cancer growth not just by decreasing tumor cell proliferation, but also by enhancing tumor necrosis. Moreover, nuclear calcium regulates tumor angiogenesis through a mechanism that involves the upregulation of the anti-angiogenic C-X-C motif chemokine 10 (CXCL10-IP10). In addition, nuclear calcium buffering regulates breast tumor cell motility, culminating in less cell invasion, likely due to enhanced vinculin expression, a focal adhesion structural protein. Together, our results show that nuclear calcium is essential for triple breast cancer angiogenesis and cell migration and can be considered as a promising strategic target for triple negative breast cancer therapy.

Highlights

Calcium (Ca2+) is a ubiquitous intracellular messenger responsible for controlling several cellular processes, including short duration events, such as contraction and secretion, as well as long-term responses such as gene transcription, proliferation and cell death [1]
In order to investigate whether nuclear Ca2+ is involved in breast tumor growth, we first evaluated the contribution of nuclear Ca2+ signals to the growth of triple negative breast cancer (TNBC)
Using time-lapse confocal microscopy, Ca2+ transients in the nucleus of 4T1, MDA-MB-231 and MDA-MB-468 cells were measured upon stimulation with epidermal growth factor (EGF), a growth factor that induces a rapid increase in calcium levels in the nucleus and cytosol of several cell types through IP3 generation [31], (Fig 1A–1G)

Summary

Introduction

Calcium (Ca2+) is a ubiquitous intracellular messenger responsible for controlling several cellular processes, including short duration events, such as contraction and secretion, as well as long-term responses such as gene transcription, proliferation and cell death [1]. IP3 binds to its specific receptor (IP3R) on the membrane of the endoplasmic reticulum and triggers Ca2+ release. IPR3 can be found in the endoplasmic reticulum, in the nuclear envelope and in the nucleus along the nucleoplasmic reticulum [2]. Ca2+ signals can propagate throughout the cell, nuclear and cytosolic Ca2+ are regulated independently and can lead to distinct cell responses [3]. Nuclear Ca2+ is well known to regulate gene transcription [4] and tumor cell proliferation in vitro and in vivo [5]. Whether nuclear Ca2+ signaling regulates additional stages of tumor progression such as cell migration and angiogenesis remains unknown

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