Selective Modulation of Endoplasmic Reticulum Stress Markers in Prostate Cancer Cells by a Standardized Mangosteen Fruit Extract

Abstract

The increased proliferation of cancer cells is directly dependent on the increased activity of the endoplasmic reticulum (ER) machinery which is responsible for protein folding, assembly, and transport. In fact, it is so critical that perturbations in the endoplasmic reticulum can lead to apoptosis. This carefully regulated organelle represents a unique target of cancer cells while sparing healthy cells. In this study, a standardized mangosteen fruit extract (MFE) was evaluated for modulating ER stress proteins in prostate cancer. Two human prostate cancer cell lines, 22Rv1 and LNCaP, and prostate epithelial cells (PrECs) procured from two patients undergoing radical prostatectomy were treated with MFE. Flow cytometry, MTT, BrdU and Western blot were used to evaluate cell apoptosis, viability, proliferation and ER stress. Next, we evaluated MFE for microsomal stability and anti-cancer activity in nude mice. MFE induced apoptosis, decreased viability and proliferation in prostate cancer cells. MFE increased the expression of ER stress proteins. Interestingly, MFE selectively promotes ER stress in prostate cancer cells while sparing PrECs. MFE suppressed tumor growth in a xenograft tumor model without obvious toxicity. Mangosteen fruit extract selectively promotes endoplasmic reticulum stress in cancer cells while sparing non-tumorigenic prostate epithelial cells. Furthermore, in an in vivo setting mangosteen fruit extract significantly reduces xenograft tumor formation.

Anti-Cancer Natural Products and Their Bioactive Compounds Inducing ER Stress-Mediated Apoptosis: A Review

“…Although significant medical and technological developments have been achieved, still conventional cancer-targeted therapies have severe side effects and complications such as serious toxicities and development of resistance [ 161 , 162 ]. Therefore, one of the major goals for cancer treatment is to find novel therapeutic approaches which make it possible to selectively kill cancer cells without harming normal cells and reduce cancer cellular resistance to chemotherapeutic agents [ 145 , 147 , 158 , 163 ].…”

“…Induction of apoptosis in PNT1a and PC3 cells through CHOP expression, triggering BH3-only proteins, AIF and cleavage of caspase-3,-9 was demonstrated by the treatment of Polyphenol E (derived from Camellia sinensis ) [ 144 ]. Mangosteen Fruit Extract (MFE; derived from Garcinia mangostana ) enhanced the level of PERK, CHOP, IRE1 and caspase-4 in both LNCaP and 22Rv1 cells through ER stress, leading to Bax and cleavage of caspase-3 [ 145 ]. Upregulation of eIF2α-ATF4-CHOP signaling and caspase-4 in PC-3, DU145, and LNCaP cells through ER stress was observed after treatment of Marchantin M (Mar; derived from Astrella angusta ) [ 146 ].…”

Gartanin, an isoprenylated xanthone from the mangosteen fruit (Garcinia mangostana), is an androgen receptor degradation enhancer

“…When UPR is unable to cope with the increased protein demand, ER stress is prolonged, and cell apoptosis is initiated. Recently, we have reported that a standardized mangosteen extract modulated the UPR pathway in prostate cancer cells . In that particular study we identified up to 26 different xanthones including gartanin in mangosteen extract.…”

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“…Recently, ER stress has been regarded as the third apoptotic pathway. α-MG was found to selectively promote ER stress so as to increase the apoptotic indices of prostate cancer cells, while exerting little influence on normal prostate epithelial cells [96,97].…”