期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE RESEARCH
DOI: 10.1038/s41467-021-20962-6
关键词
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资金
- Department of Defense Prostate Cancer Research Program (DOD PCRP) award [CCL: W81XWH1810523]
- Miles for Moffitt Foundation Award
- Core Facilities of the Moffitt Cancer Center Grant [P30-CA076292]
- Pacific Northwest Prostate Cancer SPORE [P50CA97186]
- [R50CA211447]
- U.S. Department of Defense (DOD) [W81XWH1810523] Funding Source: U.S. Department of Defense (DOD)
The authors demonstrate that MSC-derived IL-28 induces apoptosis in prostate cancer cells via IL-28R alpha -STAT1 signaling, while acquired resistance to apoptosis is associated with a shift in signaling pathway from STAT1 to STAT3 in IL-28R alpha.
Bone metastatic prostate cancer (PCa) promotes mesenchymal stem cell (MSC) recruitment and their differentiation into osteoblasts. However, the effects of bone-marrow derived MSCs on PCa cells are less explored. Here, we report MSC-derived interleukin-28 (IL-28) triggers prostate cancer cell apoptosis via IL-28 receptor alpha (IL-28R alpha)-STAT1 signaling. However, chronic exposure to MSCs drives the selection of prostate cancer cells that are resistant to IL-28-induced apoptosis and therapeutics such as docetaxel. Further, MSC-selected/IL-28-resistant prostate cancer cells grow at accelerated rates in bone. Acquired resistance to apoptosis is PCa cell intrinsic, and is associated with a shift in IL-28R alpha signaling via STAT1 to STAT3. Notably, STAT3 ablation or inhibition impairs MSC-selected prostate cancer cell growth and survival. Thus, bone marrow MSCs drive the emergence of therapy-resistant bone metastatic prostate cancer yet this can be disabled by targeting STAT3. The effects of bone-marrow derived MSCs on prostate cancer cells remain unknown. Here the authors show that MSC-derived IL-28 induces prostate cancer cell apoptosis via IL-28R alpha -STAT1 signalling, while acquired resistance to apoptosis is associated with a shift in IL-28R alpha signalling via STAT1 to STAT3.
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