MARCKSL1 exhibits anti-angiogenic effects through suppression of VEGFR-2-dependent Akt/PDK-1/mTOR phosphorylation

Abstract

Myristoylated alanine-rich C kinase substrate-like 1 (MARCKSL1) plays a pivotal role in the regulation of apoptosis and has been shown to maintain antitumor and metastasis-suppressive properties. In the present study, we examined the effects of MARCKSL1 as a novel anti-angiogenic agent on the inhibition of angiogenesis-mediated cell migration. MARCKSL1 also reduced vascular endothelial growth factor (VEGF)-induced human umbilical vein endothelial cell (HUVEC) proliferation, as well as capillary-like tubular structure formation in vitro. MARCKSL1 disrupted phosphorylation of vascular endothelial growth factor receptor-2 (VEGFR-2) in ovarian tumorigenesis. In addition, MARCKSL1 showed potent anti-angiogenic activity and reduced the levels of VEGF and hypoxia-inducible factor 1α (HIF-1α) expression, an essential regulator of angiogenesis. Consistently, MARCKSL1 decreased VEGF‑induced phosphorylation of the PI3K/Akt signaling pathway components, including phosphoinositide-dependent protein kinase 1 (PDK-1), mammalian target of rapamycin (mTOR), tuberous sclerosis complex 2 (TSC-2), p70 ribosomal protein S6 kinase (p70S6K), and glycogen synthase kinase 3β (GSK-3β) protein. Collectively, our results provide evidence for the physiological/biological function of an endothelial cell system involved in angiogenesis through suppression of Akt/PDK-1/mTOR phosphorylation by interaction with VEGFR-2.

ELL targets c-Myc for proteasomal degradation and suppresses tumour growth

“…15D ). S100A4 , MARCKSL1 and BAG4 have been reported to play important roles in promoting tumour metastasis 39 40 41 42 43 44 45 46 47 48 . Thus, ELL(C595A) mutant might promote tumour metastasis through inducing these metastasis-associated genes.…”

“…In addition, silencing of S100A4 via siRNA or shRNA and blocking of S100A4 via anti-S100A4 antibody can reduce metastasis formation by blocking stroma cell invasion 41 42 43 . MARCKSL1 exhibits anti-angiogenic effects through suppression of VEGFR-2-dependent Akt/PDK-1/mTOR phosphorylation 45 . BAG4 is a negative regulator of apoptosis, which also links to tumour aggressiveness and metastasis 47 48 .…”

MicroRNA-132 modifies angiogenesis in patients with ischemic cerebrovascular disease by suppressing the NF‑κB and VEGF pathway

“…It has a serious effect on the health and life of patients, is a burden to the family and society, and inflicts substantial social and economic costs (3). According to the data of one survey, it possesses the highest disability and mortality rate in China (4). The incidence rate is rising at an annual growth rate of 8.7%, reflecting China's aging population (1).…”

MARCKS-related protein regulates cytoskeletal organization at cell–cell and cell–substrate contacts in epithelial cells

“…In addition to the defect in cell spreading, we also noted that MRP-KO cells migrated more slowly than WT cells. Although a number of studies have demonstrated both stimulatory and inhibitory roles for MRP in cell migration, in some cases dependent on site-specific MRP phosphorylation, the consensus is that, as we found, MRP depletion is associated with decreased migration (Chun et al, 2009;Finlayson and Freeman, 2009;Bjorkblom et al, 2012;Kim et al, 2016). Although the mechanism causing the decreased migration is unclear, delayed migration is also seen in FAK-KO cells, where it is also thought to be related to defective focal adhesion remodeling (Schober et al, 2007).…”