4-1BBL has a Possible Role in Mediating Castration-Resistant Conversion of Prostate Cancer via Up-Regulation of Androgen Receptor.

Abstract

4-1BB ligand (4-1BBL) was a transmembrane glycoprotein belonging to the tumor necrosis factor family. It was expressed on activated T lymphocytes and function as a co-stimulatory molecule via cross-linking with 4-1BB (a.k.a, CD137). In addition to its role in immune regulation, 4-1BBL transmitted signals into the cells on which it was expressed (reverse signaling). 4-1BBL represented a promising target for enhancing antitumor immune responses. Recent studies indicated that 4-1BBL also expressed in non-immune cells and possessed different functions in various types of cells. Here, we reported that 4-1BBL didn't express in normal prostate tissues and benign prostatic hyperplasia tissues, but it expressed in prostate cancer (PCa) tissues at moderate level. Expression of 4-1BBL was up-regulated during the transition from PCa to castration resistant prostate cancer (CRPC). Increasing expression of 4-1BBL not only promoted expression of androgen receptor (AR), but also augmented proliferation and invasion ability of prostate cancer cells in androgen deprivation environment. These results were further verified by xenograft tumor experiments. Meanwhile, inhibiting AR signal pathway by chemical antagonist was able to significantly reduce 4-1BBL mediated proliferation and invasion of PCa cells. These novel findings indicated that 4-1BBL might mediate prostate cancer progression to castration-resistant prostate cancer via enhancing expression and function of AR.