Downregulation of class II phosphoinositide 3-kinase PI3K-C2β delays cell division and potentiates the effect of docetaxel on cancer cell growth

Autor: Ambisha Sarvananthan, Federico Gulluni, Tania Maffucci, Methushaa Suthanthirakumaran, Emilio Hirsch, Lara C. R. Oh, Ioanna Mavrommati, Jessica N. Schlatter, Federica Guffanti, Ouma Cisse, Massimo Broggini, Muzthahid Quraishi, Marco Falasca
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Male
Cancer Research
PI3K-C2β
Cell
Mitosis
Down-Regulation
Mice
Nude
Uterine Cervical Neoplasms
Antineoplastic Agents
Docetaxel
Phosphoinositide 3-kinase
Transfection
lcsh:RC254-282
HeLa
03 medical and health sciences
Random Allocation
0302 clinical medicine
Downregulation and upregulation
medicine
Animals
Humans
Clonogenic assay
Cell Proliferation
Class II Phosphatidylinositol 3-Kinases
Prostate cancer
biology
Chemistry
Cell growth
Research
Prostatic Neoplasms
Cell cycle
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
biology.organism_classification
Xenograft Model Antitumor Assays
030104 developmental biology
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
Cancer cell
PC-3 Cells
Cancer research
Female
Cell Division
medicine.drug
HeLa Cells
Zdroj: Journal of Experimental & Clinical Cancer Research : CR
Journal of Experimental & Clinical Cancer Research, Vol 38, Iss 1, Pp 1-19 (2019)
ISSN: 1756-9966
0392-9078
Popis: Background Alteration of signalling pathways regulating cell cycle progression is a common feature of cancer cells. Several drugs targeting distinct phases of the cell cycle have been developed but the inability of many of them to discriminate between normal and cancer cells has strongly limited their clinical potential because of their reduced efficacy at the concentrations used to limit adverse side effects. Mechanisms of resistance have also been described, further affecting their efficacy. Identification of novel targets that can potentiate the effect of these drugs or overcome drug resistance can provide a useful strategy to exploit the anti-cancer properties of these agents to their fullest. Methods The class II PI3K isoform PI3K-C2β was downregulated in prostate cancer PC3 cells and cervical cancer HeLa cells using selective siRNAs and the effect on cell growth was determined in the absence or presence of the microtubule-stabilizing agent/anti-cancer drug docetaxel. Mitosis progression was monitored by time-lapse microscopy. Clonogenic assays were performed to determine the ability of PC3 and HeLa cells to form colonies upon PI3K-C2β downregulation in the absence or presence of docetaxel. Cell multi-nucleation was assessed by immunofluorescence. Tumour growth in vivo was assessed using a xenograft model of PC3 cells upon PI3K-C2β downregulation and in combination with docetaxel. Results Downregulation of PI3K-C2β delays mitosis progression in PC3 and HeLa cells, resulting in reduced ability to form colonies in clonogenic assays in vitro. Compared to control cells, PC3 cells lacking PI3K-C2β form smaller and more compact colonies in vitro and they form tumours more slowly in vivo in the first weeks after cells implant. Stable and transient PI3K-C2β downregulation potentiates the effect of low concentrations of docetaxel on cancer cell growth. Combination of PI3K-C2β downregulation and docetaxel almost completely prevents colonies formation in clonogenic assays in vitro and strongly inhibits tumour growth in vivo. Conclusions These data reveal a novel role for the class II PI3K PI3K-C2β during mitosis progression. Furthermore, data indicate that blockade of PI3K-C2β might represent a novel strategy to potentiate the effect of docetaxel on cancer cell growth.
Databáze: OpenAIRE
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