Role of intracellular prostaglandin E2 in cancer-related phenotypes in PC3 cells

Intracrine prostaglandin E2 pro‐tumoral actions in prostate epithelial cells originate from non‐canonical pathways

“…The effects of PGE 2 on non‐transformed prostate epithelial cells are currently unknown, despite they may be relevant in non‐malignant proliferative diseases of the prostate associated with chronic inflammation of the prostate such are BPH or proliferative inflammatory atrophy (Bardan, Dumache, Dema, Cumpanas, & Bucuras, ; Thapa & Ghosh, ). Here we found in immortalized, non‐malignant prostate epithelial RWPE‐1 cells that PGE 2 , again through the axis iPGE 2 ‐iEP receptors‐EGFR‐HIF‐1α, inhibits cell adhesion and stimulates cell proliferation, migration and in vitro angiogenesis (i.e., the same effects than in PC3 cells (Fernández‐Martínez & Lucio‐Cazaña, ; Madrigal‐Martínez et al, )). Since iPGE 2 mediates the growth‐stimulating effects of PGE 2 on prostate epithelial cells, regardless they are benign or malign ones, the pharmacological inhibition of PGT could be a novel therapeutic approach to treat prostate proliferative diseases associated with chronic inflammation.…”

“…PGE 2 can directly bind to its receptors on tumor cells to regulate cell proliferation, apoptosis, migration and invasion as well as to induce tumor cells to secrete growth factors, pro‐inflammatory mediators, and angiogenic factors that stimulate angiogenesis and local inflammation (Wang & DuBois, ). Most of these PGE 2 effects have also been specifically documented in PC cells (Huang et al, ; Jain, Chakraborty, Raja, Kale, & Kundu, ; Jiang & Dingledine, ; Madrigal‐Martínez, Lucio‐Cazaña, & Fernández‐Martínez, ; Vo et al, ; Wang & Klein, ).…”

“…It is generally accepted that the biological actions of PGE 2 are mediated by plasma membrane G protein‐coupled EP receptors which are located at the cell membrane. However, we have found that PGE 2 has to reach the intracellular compartment and activate a subset of EP receptors, which is located intracellularly, as a prerequisite for being effective in PC3 cells (Fernández‐Martínez & Lucio‐Cazaña, ; Madrigal‐Martínez et al, ). This is a non‐canonical intracrine mechanism of PGE 2 action for which the energetically active influx of PGE 2 (accounting for almost 100% of PGE 2 internalization), is mediated by the prostaglandin transporter (PGT), a member of the organic anion transporter family (Nomura, Lu, Pucci, & Schuster, ; Schuster, ).…”

“…This is a non‐canonical intracrine mechanism of PGE 2 action for which the energetically active influx of PGE 2 (accounting for almost 100% of PGE 2 internalization), is mediated by the prostaglandin transporter (PGT), a member of the organic anion transporter family (Nomura, Lu, Pucci, & Schuster, ; Schuster, ). Once PGE 2 is internalized in PC3 cells and becomes intracellular PGE 2 (iPGE 2 ), it inhibits cell adhesion and stimulates cell proliferation, migration and in vitro angiogenesis (Fernández‐Martínez & Lucio‐Cazaña, ; Madrigal‐Martínez et al, ). The mechanism involves transactivation of epidermal growth factor‐receptor (EGFR) by iEP, leading to increased expression and activity of hypoxia‐inducible factor‐1α (HIF‐1α) (Fernández‐Martínez & Lucio‐Cazaña, ).…”

“…and angiogenic factors that stimulate angiogenesis and local inflammation (Wang & DuBois, 2013). Most of these PGE 2 effects have also been specifically documented in PC cells (Huang et al, 2013;Jain, Chakraborty, Raja, Kale, & Kundu, 2008;Jiang & Dingledine, 2013;Madrigal-Martínez, Lucio-Cazaña, & Fernández-Martínez, 2015;Vo et al, 2013;Wang & Klein, 2007).…”