Increased fatty acyl saturation of phosphatidylinositol phosphates in prostate cancer progression

Atsushi Koizumi,Masaki Ishikawa,Takamitsu Inoue,Hiroki Nakanishi,Tomonori Habuchi,Junko Sasaki,Mingguo Huang,Takehiko Sasaki,Toshiaki Yoshioka,Shunsuke Takasuga,Shintaro Narita,Hirotaka Kimura,Satoshi Eguchi

doi:10.1038/s41598-019-49744-3

Abstract

Phosphoinositides (PIPs) participate in many cellular processes, including cancer progression; however, the metabolic features of PIPs associated with prostate cancer (PCa) are unknown. We investigated PIPs profiles in PTEN-deficient prostate cancer cell lines, human prostate tissues obtained from patients with PCa and benign prostate hyperplasia (BPH) specimens using mass spectrometry. In immortalized normal human prostate PNT1B cells, PTEN deficiency increased phosphatidylinositol tris-phosphate (PIP3) and decreased phosphatidylinositol mono- and bis-phosphate (PIP1 and PIP2), consistent with PTEN’s functional role as a PI(3,4,5)P3 3-phosphatase. In human prostate tissues, levels of total (sum of all acyl variants) phosphatidylinositol (PI) and PIP1 in PCa were significantly higher than in BPH, whereas PIP2 and PIP3 contents were significantly lower than in BPH. PCa patients had significantly higher proportion of PI, PIP1, and PIP2 with 0–2 double bonds in acyl chains than BPH patients. In subgroup analyses based on PCa aggressiveness, mean total levels of PI with 0–2 double bonds in acyl chains were significantly higher in patients with pathological stage T3 than in those with pathological stage T2. These data indicate that alteration of PIPs level and the saturation of acyl chains may be associated with the development and aggressiveness of prostate cancer, although it is unknown whether this alteration is causative.

Highlights

Prostate cancer (PCa) is one of the most common malignancies in men worldwide[1]
We examined the levels of PIPs by a reverse phase LC/MS/MS method that allows quantitation of PI, PIP1, PIP2 (as the sum of PI(3,4)P2, PI(3,5)P2, and PI(4,5)P2), and PIP3
6.5 ± 0.7 18.7 ± 3.6 282.2 ± 32.6 345.2 ± 50.9 3.1 ± 0.5 3.5 ± 0.3 7.0 ± 1.4 11.7 ± 2.4 p value 0.065 0.765 0.547 0.004 0.302 0.265 0.571 0.169 0.878. This is the first report demonstrating the changes in PIPs, including PI, PIP1, PIP2 and PIP3, at the acyl species level in human benign prostate hyperplasia (BPH) and prostate cancer (PCa)

Summary

Introduction

Prostate cancer (PCa) is one of the most common malignancies in men worldwide[1]. Epidemiological studies have shown that systematic metabolic disorders and fat-rich diets might increase the risk of developing PCa2. Lipid metabolism and its related molecules play an important role in human cancers, including PCa, by modulating numerous cellular processes[3,4]. Signalling by phosphoinositides (PIPs) using a lipid messenger cascade involving a family of minor acidic phospholipids in cell membranes regulates a substantial number of intracellular proteins with various functions[5,6,7]. The expression profile and impact of lipid acyl chains in PCa have remained largely unknown. We investigate PIPs profiles in PCa using preclinical prostate cells and human PCa tissues using an original method utilising mass spectrometry. Patterns including PIP1, PIP2 and PIP3, as well as their acyl chain profiles, in preclinical prostate cells and clinical PCa specimens. We thereby successfully confirm PIPs changes in PCa using in vitro PTEN-driven preclinical PCa models and show specific features of PIPs levels in human PCa compared with benign prostate tissues

Methods

Results

Conclusion