Inhibition of Vps34 and p110δ PI3K Impairs Migration, Invasion and Three-Dimensional Spheroid Growth in Breast Cancer Cells

Abstract

Breast cancer is a heterogeneous disease that represents the most common cancer around the world; it comprises 12% of new cases according to the World Health Organization. Despite new approaches in early diagnosis and current treatment, breast cancer is still the leading cause of death for cancer mortality. New targeted therapies against key signalling transduction molecules are required. Phosphoinositide 3-kinase (PI3K) regulates multiple biological functions such as proliferation, survival, migration, and growth. It is well established that PI3K isoform-selective inhibitors show fewer toxic side effects compared to broad spectrum inhibition of PI3K (pan-PI3K inhibitors). Therefore, we tested the PI3K p110δ-selective inhibitor, IC87114, and Vps34-selective inhibitor, Vps34-IN1, on the breast cancer cell lines MCF-7 and MDA-MB-231, representing hormone-responsive and triple-negative breast cancer cells, respectively. Our data show that both inhibitors decreased migration of MCF-7 and MDA-MB-231 cells, and Vps34 also significantly impacted MCF-7 cell proliferation. Three-dimensional (3D) in vitro culture models show that IC87114 and Vps34-IN1 treatment reduced the growth of MCF-7 and MDA-MB-231 cells in 3D tumour spheroid cultures. This study identifies IC87114 and Vps34-IN1 as potential therapeutic approaches in breast cancer.

Aberrant PI3Kδ splice isoform as a potential biomarker and novel therapeutic target for endocrine cancers

“…Emerging evidence has revealed that PI3Kδ is expressed not only in hematologic cancers, but also highly expressed in solid tumors ( 16 – 18 ). Particularly, previous studies have shown that PI3Kδ is overexpressed in PCa cell lines (DU-145, 22Rv1, PC-3 ( 18 ), LNCaP and MDA PCa 2b ( 33 )), breast cancer lines (MDA MB 231 and MCF-7 ( 22 )), colon cancer lines (SW620 and SW480 ( 40 )) and lung cancer cell lines (A549, H1975, PC9 and H1650 ( 41 )). Consistent with the previous studies, our data again confirmed that PI3Kδ is expressed in LNCaP, DU-145, PC-3, 22Rv1, MDA PCa 2b, MDA MB 231, MCF-7, SW620 and A549.…”

“…PI3Kδ has also been shown to regulate the biochemical and bioinformatic properties of breast cancers. For instance, upregulation of PI3Kδ promotes cell migration, invasion, and spheroid growth of breast cancer cell lines ( 22 , 23 ). Overexpression of PI3Kδ was also detected in primary neuroblastomas and cell lines.…”

Tumor microenvironment-responsive micelles assembled from a prodrug of mitoxantrone and 1-methyl tryptophan for enhanced chemo-immunotherapy

“…MCF-7/ADR cells were seeded into the 96-well plate at 5 × 10 3 /well and cultured in an incubator. Tumor spheroids (Di Donato et al., 2022 ) of appropriate shape and size were selected and treated with MX, PEG-SS-MX-1-MT, and PEG-SS-MX-1-MT/FA at a MX concentration of 1 μg/mL. In the next 5 days, 3D tumor spheroids were photographed using an optical microscope (Eclipse E400; Nikon, Tokyo, Japan).…”

“…After incubation for 48 h, the wound area was photographed using a microplate reader. Cell migration in the treatment groups was analyzed (Yang et al., 2018 ; Di Donato et al., 2022 ).…”

VPS34-IN1 inhibits cap-mediated translation and synergizes with STING to drive type-I IFN expression in human plasmacytoid DCs

“…Given the critical roles of these pathways in tumor development and growth and the availability of potent pharmacological inhibitors ( 9 , 10 ), the inhibition of VPS34 has emerged as a promising chemotherapeutic strategy for leukemia and breast cancer treatment ( 11 , 12 ). Inhibition of PtdIns(3)P production, also impinges on specialized functions in immune cells requiring endocytosis and autophagy.…”