Implication of calcium activated RasGRF2 in Annexin A6-mediated breast tumor cell growth and motility.

Autor:	Whalen DS; Department of Biochemistry and Cancer Biology, School of Graduate Studies and Research, Meharry Medical College, Nashville, TN, USA., Widatalla SE; Department of Biochemistry and Cancer Biology, School of Graduate Studies and Research, Meharry Medical College, Nashville, TN, USA., Korolkova OY; Department of Biochemistry and Cancer Biology, School of Graduate Studies and Research, Meharry Medical College, Nashville, TN, USA., Nangami GS; Department of Biochemistry and Cancer Biology, School of Graduate Studies and Research, Meharry Medical College, Nashville, TN, USA., Beasley HK; Department of Biochemistry and Cancer Biology, School of Graduate Studies and Research, Meharry Medical College, Nashville, TN, USA., Williams SD; Department of Biochemistry and Cancer Biology, School of Graduate Studies and Research, Meharry Medical College, Nashville, TN, USA., Virgous C; Animal Care Facility, Meharry Medical College, Nashville, TN, USA., Lehmann BD; Department of Biochemistry, Vanderbilt University, Nashville, TN, USA., Ochieng J; Department of Biochemistry and Cancer Biology, School of Graduate Studies and Research, Meharry Medical College, Nashville, TN, USA., Sakwe AM; Department of Biochemistry and Cancer Biology, School of Graduate Studies and Research, Meharry Medical College, Nashville, TN, USA.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2019 Jan 04; Vol. 10 (2), pp. 133-151. Date of Electronic Publication: 2019 Jan 04 (Print Publication: 2019).
DOI:	10.18632/oncotarget.26512
Abstrakt:	The role of AnxA6 in breast cancer and in particular, the mechanisms underlying its contribution to tumor cell growth and/or motility remain poorly understood. In this study, we established the tumor suppressor function of AnxA6 in triple negative breast cancer (TNBC) cells by showing that loss of AnxA6 is associated with early onset and rapid growth of xenograft TNBC tumors in mice. We also identified the Ca 2+ activated RasGRF2 as an effector of AnxA6 mediated TNBC cell growth and motility. Activation of Ca 2+ mobilizing oncogenic receptors such as epidermal growth factor receptor (EGFR) in TNBC cells or pharmacological stimulation of Ca 2+ influx led to activation, subsequent degradation and altered effector functions of RasGRF2. Inhibition of Ca 2+ influx or overexpression of AnxA6 blocked the activation/degradation of RasGRF2. We also show that AnxA6 acts as a scaffold for RasGRF2 and Ras proteins and that its interaction with RasGRF2 is modulated by GTP and/or activation of Ras proteins. Meanwhile, down-regulation of RasGRF2 and treatment of cells with the EGFR-targeted tyrosine kinase inhibitor (TKI) lapatinib strongly attenuated the growth of otherwise EGFR-TKI resistant AnxA6 high TNBC cells. These data not only suggest that AnxA6 modulated Ca 2+ influx and effector functions of RasGRF2 underlie at least in part, the AnxA6 mediated TNBC cell growth and/or motility, but also provide a rationale to target Ras-driven TNBC with EGFR targeted therapies in combination with inhibition of RasGRF2. Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.
Databáze:	MEDLINE
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