Mammalian target of rapamycin (mTOR) regulates various fundamental cellular events including cell proliferation,
protein synthesis, metabolism, apoptosis, and autophagy.
Tumor suppressive miR-99b-5p has been implicated in regulating PI3K/AKT/mTOR signaling in a variety of types of
cancer. Our previous study suggested the reciprocal miR-99b-5p/MTOR (downregulated/upregulated) pairing as a key
microRNA-
mRNA regulatory component involved in the
prostate cancer (PCa) disparities. In this study, we further validated the expression profiles of mTOR and miR-99b-5p in the PCa, colon, breast, and
lung cancer specimens and cell lines. The immunohistochemistry (IHC), immunofluorescence, Western blot, and RT-qPCR assays have confirmed that mTOR is upregulated while miR-99b-5p is downregulated in different patient cohorts and a panel of
cancer cell lines. Intriguingly, elevated nuclear mTOR expression was observed in African American PCa and other advanced
cancers. Transfection of the miR-99b-5p mimic resulted in a significant reduction in nuclear mTOR and
androgen receptor (AR), while a slight/moderate to no decrease in cytoplasmic mTOR and AR in PCa and other
cancer cells, suggesting that miR-99b-5p inhibits mTOR and AR expression and their nuclear translocation. Moreover, overexpression of miR-99b-5p targets/inhibits AR-mTOR axis, subsequently initiating cell apoptosis and sensitizing
docetaxel-induced cytotoxicity in various
cancers. In conclusion, our data suggest that reciprocal miR-99b-5p/nuclear mTOR pairing may be a more precise diagnostic/prognostic
biomarker for aggressive PCa, than miR-99b-5p/MTOR pairing or mTOR alone. Targeting the AR-mTOR axis using miR-99b-5p has also been suggested as a novel therapeutic strategy to induce apoptosis and overcome chemoresistance in aggressive PCa.