An anionic phthalocyanine decreases NRAS expression by breaking down its RNA G-quadruplex

Keiko Kawauchi (), Wataru Sugimoto, Takatoshi Yasui, Kohei Murata, Katsuhiko Itoh, Kazuki Takagi, Takaaki Tsuruoka, Kensuke Akamatsu, Hisae Tateishi-Karimata, Naoki Sugimoto and Daisuke Miyoshi ()
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Keiko Kawauchi: Konan University
Wataru Sugimoto: Konan University
Takatoshi Yasui: Konan University
Kohei Murata: Konan University
Katsuhiko Itoh: Konan University
Kazuki Takagi: Konan University
Takaaki Tsuruoka: Konan University
Kensuke Akamatsu: Konan University
Hisae Tateishi-Karimata: Konan University
Naoki Sugimoto: Konan University
Daisuke Miyoshi: Konan University

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: Abstract Aberrant activation of RAS signalling pathways contributes to aggressive phenotypes of cancer cells. The RAS-targeted therapies for cancer, therefore, have been recognised to be effective; however, current developments on targeting RAS have not advanced due to structural features of the RAS protein. Here, we show that expression of NRAS, a major isoform of RAS, can be controlled by photo-irradiation with an anionic phthalocyanine, ZnAPC, targeting NRAS mRNA. In vitro experiments reveal that ZnAPC binds to a G-quadruplex–forming oligonucleotide derived from the 5′-untranslated region of NRAS mRNA even in the presence of excess double-stranded RNA, which is abundant in cells, resulting in selective cleavage of the target RNA’s G-quadruplex upon photo-irradiation. In line with these results, upon photo-irradiation, ZnAPC decreases NRAS mRNA and NRAS expression and thus viability of cancer cells. These results indicate that ZnAPC may be a prominent photosensitiser for a molecularly targeted photodynamic therapy for cancer.

Date: 2018
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DOI: 10.1038/s41467-018-04771-y

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