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Inhibition of mitochondria ATP synthase suppresses prostate cancer growth through reduced insulin‐like growth factor‐1 secretion by prostate stromal cells
Author(s) -
Ohishi Tomokazu,
Abe Hikaru,
Sakashita Chiharu,
Saqib Uzma,
Baig Mirza S.,
Ohba Shunichi,
Inoue Hiroyuki,
Watanabe Takumi,
Shibasaki Masakatsu,
Kawada Manabu
Publication year - 2020
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32959
Subject(s) - stromal cell , mitochondrion , atp synthase , insulin like growth factor , prostate , growth factor , biology , prostate cancer , cancer research , adenosine triphosphate , cancer cell , endocrinology , microbiology and biotechnology , medicine , chemistry , cancer , biochemistry , enzyme , receptor
Modulation of prostate stromal cells (PrSCs) within tumor tissues is gaining attention for the treatment of solid tumors. Using our original in vitro coculture system, we previously reported that leucinostatin (LCS)‐A, a peptide mycotoxin, inhibited prostate cancer DU‐145 cell growth through reduction of insulin‐like growth factor 1 (IGF‐I) expression in PrSCs. To further obtain additional bioactive compounds from LCS‐A, we designed and synthesized a series of LCS‐A derivatives as compounds that target PrSCs. Among the synthesized LCS‐A derivatives, LCS‐7 reduced IGF‐I expression in PrSCs with lower toxicity to PrSCs and mice than LCS‐A. As LCS‐A has been suggested to interact with mitochondrial adenosine triphosphate (ATP) synthase, a docking study was performed to elucidate the mechanism of reduced IGF‐I expression in the PrSCs. As expected, LCS‐A and LCS‐7 directly interacted with mitochondrial ATP synthase, and like LCS‐A and LCS‐7, other mitochondrial ATP synthase inhibitors also reduced the expression of IGF‐I by PrSCs. Furthermore, LCS‐A and LCS‐7 significantly decreased the growth of mouse xenograft tumors. Based on these data, we propose that the mitochondrial ATP synthases–IGF‐I axis of PrSCs plays a critical role on cancer cell growth and inhibition could be a potential anticancer target for prostate cancer.