Molecular circuit involving KLK4 integrates androgen and mTOR signaling in prostate cancer

• Type: Article in International Scientific Journal
• Date: 2013

Authors

Jin, Y (Author) Other; Qu, S (Author) Other; Tesikova, M (Author) Other; Wang, L (Author) Other; Kristian, A (Author) Other; Maelandsmo, GM (Author) Other; Kong, HY (Author) Other; Zhang, TZ (Author) Other; Carmen Jeronimo (Author) ICBAS; Manuel R Teixeira (Author) ICBAS; Yuca, E (Author) Other; Tekedereli, I (Author) Other; Gorgulu, K (Author) Other; Alpay, N (Author) Other; Sood, AK (Author) Other; Lopez Berestein, G (Author) Other; Danielsen, HE (Author) Other; Ozpolat, B (Author) Other; Saatcioglu, F (Author) Other

Journal

Title: Proceedings of the National Academy of Sciences of the United States of America

Vol. 110

ISSN: 0027-8424

Publisher: National Academy of Sciences

Indexing

ISI Web of Knowledge - 48 Citations

Scopus - 47 Citations

Other information

Authenticus ID: P-006-97Z

DOI: 10.1073/pnas.1304318110

Abstract (EN): The androgen receptor (AR) and the phosphoinositide 3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin (mTOR) signaling are two of the major proliferative pathways in a number of tissues and are the main therapeutic targets in various disorders, including prostate cancer (PCa). Previous work has shown that there is reciprocal feedback regulation of PI3K and AR signaling in PCa, suggesting that cotargeting both pathways may enhance therapeutic efficacy. Here we show that proteins encoded by two androgen-regulated genes, kallikrein related peptidase 4 (KLK4) and promyelocytic leukemia zinc finger (PLZF), integrate optimal functioning of AR and mTOR signaling in PCa cells. KLK4 interacts with PLZF and decreases its stability. PLZF in turn interacts with AR and inhibits its function as a transcription factor. PLZF also activates expression of regulated in development and DNA damage responses 1, an inhibitor of mTORC1. Thus, a unique molecular switch is generated that regulates both AR and PI3K signaling. Consistently, KLK4 knockdown results in a significant decline in PCa cell proliferation in vitro and in vivo, decreases anchorage-independent growth, induces apoptosis, and dramatically sensitizes PCa cells to apoptosis-inducing agents. Furthermore, in vivo nanoliposomal KLK4 siRNA delivery in mice bearing PCa tumors results in profound remission. These results demonstrate that the activities of AR and mTOR pathways are maintained by KLK4, which may thus be a viable target for therapy.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 10