Androgen-deprivation therapy (ADT) is standard treatment for locally advanced or metastatic prostate cancer (PCa). Many patients develop castration resistance (castration-resistant PCa [CRPC]) after approximately 2-3 yr, with a poor prognosis. The molecular mechanisms underlying CRPC progression are unclear. To undertake quantitative tumour transcriptome profiling prior to and following ADT to identify functionally important androgen-regulated pathways or genes that may be reactivated in CRPC. RNA sequencing (RNA-seq) was performed on tumour-rich, targeted prostatic biopsies from seven patients with locally advanced or metastatic PCa before and approximately 22 wk after ADT initiation. Differentially regulated genes were identified in treatment pairs and further investigated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) on cell lines and immunohistochemistry on a separate CRPC patient cohort. Functional assays were used to determine the effect of pathway modulation on cell phenotypes. We searched for gene expression changes affecting key cell signalling pathways that may be targeted as proof of principle in a CRPC in vitro cell line model. We identified ADT-regulated signalling pathways, including the Wnt/β-catenin signalling pathway, and observed overexpression of β-catenin in a subset of CRPC by immunohistochemistry. We validated 6 of 12 (50%) pathway members by qRT-PCR on LNCaP/LNCaP-AI cell RNAs, of which 4 (67%) demonstrated expression changes consistent with RNA-seq data. We show that the tankyrase inhibitor XAV939 (which promotes β-catenin degradation) reduced androgen-independent LNCaP-AI cell line growth compared with androgen-responsive LNCaP cells via an accumulation of cell proportions in the G0/G1 phase and reduction in the S and G2/M phases. Our biopsy protocol did not account for tumour heterogeneity, and pathway inhibition was limited to pharmacologic approaches. RNA-seq of paired PCa samples revealed ADT-regulated signalling pathways. Proof-of-principle inhibition of the Wnt/β-catenin signalling pathway specifically delays androgen-independent PCa cell cycle progression and proliferation and warrants further investigation as a potential target for therapy for CRPC.

Significance: Using an unbiased forward mutagenesis screen, we were able to successfully identify candidate genes that drive advanced and metastatic prostate cancer (CaP). Alterations of peroxisome proliferator-activated receptor gamma (PPARG), encoding a regulator crucial of lipid metabolism, appear to play a role in the development of metastatic CaP in both humans and mice.

This study reviews the importance of resistant starch (RS) as the polymer of choice for biodegradable food packaging and highlights the RS types and modification methods for developing RS from native starch (NS). NS is used in packaging because of its vast availability, low cost and film forming capacity. However, application of starch is restricted due to its high moisture sensitivity and hydrophilic nature. The modification of NS into RS improves the film forming characteristics and extends the applications of starch into the formulation of packaging. The starch is blended with other bio-based polymers such as guar, konjac glucomannan, carrageenan, chitosan, xanthan gum and gelatin as well as active ingredients such as nanoparticles (NPs), plant extracts and essential oils to develop hybrid biodegradable packaging with reduced water vapor permeability (WVP), low gas transmission, enhanced antimicrobial activity and mechanical properties. Hybrid RS based active packaging is well known for its better film forming properties, crystalline structures, enhanced tensile strength, water resistance and thermal properties. This review concludes that RS, due to its better film forming ability and stability, can be utilized as polymer of choice in the formulation of biodegradable packaging.