Stromal cell-derived small extracellular vesicles enhance radioresistance of prostate cancer cells via interleukin-8-induced autophagy

Abstract

Radiation is a curative treatment for localized prostate cancer (PCa). Unfortunately, radiotherapeutic efficacy is often diminished when patients develop more aggressive or metastatic phenotypes. Recent studies have demonstrated that extracellular vesicles participate in cancer therapeutic resistance by delivering small bioactive molecules, such as small non-coding RNAs. Here, we show that stromal cell-derived small extracellular vesicles (sEVs) facilitate the radioresistance of PCa cells by transporting interleukin-8 (IL-8). Indeed, prostatic stromal cells secrete more IL-8 than AR-positive PCa cells, which can be accumulated in sEVs. Intriguingly, the uptake of stromal cells-derived sEVs by radiosensitive PCa cells enhanced their radioresistance, which could be attenuated by silencing CXCL8 in stromal cells or inhibiting its receptor CXCR2 in PCa cells. sEV-mediated radioresistance has been validated in zebrafish and mouse xenograft tumours. Mechanistically, the uptake of stromal sEVs triggers the AMPK-activated autophagy pathway in PCa cells under the irradiation condition. Consequently, inactivating AMPK efficiently resensitized radiotherapy either by utilizing an AMPK inhibitor or silencing AMPKα in PCa cells. Furthermore, chloroquine (CQ), a lysosomal inhibitor, sufficiently resensitized radiotherapy via blockade of autophagolysosome fusion, leading to autophagosome accumulation in PC cells. Collectively, these results suggest that stromal cells enhance the radioresistance of PCa cells mainly through sEVs that deliver IL-8.

Keywords: AMPK; autophagy; chloroquine; interleukin-8; prostate cancer; radioresistance; small extracellular vesicles; stromal cells.