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Adenine Induces Apoptosis Markers in B16-F10 Melanoma Cells: Inhibiting Akt and mTOR and Increasing Bax/Bcl-2 Ratio
Biomed Sci Letters 2023;29:201-205
Published online September 30, 2023;  https://doi.org/10.15616/BSL.2023.29.3.201
© 2023 The Korean Society For Biomedical Laboratory Sciences.

Seung-Kiel Park†,*

Department of Biochemistry, College of Medicine, Chungnam National University, Daejeon 35015, Korea
Correspondence to: Seung-Kiel Park. Department of Biochemistry, College of Medicine, Chungnam National University, Daejeon 35015, Korea.
Tel: +82-42-580-8224, Fax: +82-42-580-8121, e-mail: parksk@cnu.ac.kr
*Professor.
Received July 21, 2023; Revised August 8, 2023; Accepted August 8, 2023.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
 Abstract
Free adenine is mainly made during the polyamine synthesis in proliferating cells. Adenine molecule itself acts biological modulator in inflammation and cell death. In the previous report, we showed that adenine induces apoptotic cell death of B16-F10 mouse melanoma cells by eliciting of PARP and caspase 3 cleavages. In this study, we examined the adenine effect on other apoptotic molecules affecting caspase activation in B16-F10 melanoma cells. Adenine treatment make pro-apoptotic molecules active states. Bax/Bcl-2 ratio was increased and phosphorylation of mTOR and Akt was decreased in a dose dependent manner. These results showed the possibility that Bax/Bcl-2, Akt and mTOR are engaged in adenine induced apoptosis of melanoma cells.
Keywords : Adenine, Melanoma, Apoptosis, Bcl-2, Akt, mTOR
꽌 濡

벂由 뿼湲곗씤 븘뜲땶 빑궛쓽 援ъ꽦 遺꾩옄씠떎. 븘뜲땶 빀꽦 빑궛 遺꾪빐 怨쇱젙뿉꽌 留뚮뱾뼱吏吏 븡怨, 二쇰줈 뤃由 븘誘 빀꽦 怨쇱젙뿉꽌 깮꽦릺뒗 5'-methylthioadenosine (MTA)뿉꽌 留뚮뱾뼱吏꾨떎(Avila et al., 2004). 利앹떇븯뒗 由쇳봽븘꽭룷뿉꽌 留뚮뱾뼱吏뒗 븘뜲땶쓽 85% 씠긽 MTA뿉꽌 留뚮뱾뼱吏꾨떎(Kamatani and Carson, 1981). 븘뜲땶 援ъ젣諛섏쓳쓣 넻빐 AMP濡 諛붾뚯뼱 ADP ATP瑜 깮꽦븳떎. 븘뜲땶 띁궓젣꽭룷 삁援ъ꽭룷쓽 깮議댁쓣 利앷떆궎硫(Watanabe et al., 2003; Simon et al., 1962), 諛섎㈃뿉 由쇳봽븘꽭룷쓽 꽦옣쓣 뼲젣븳떎(Hershfield et al., 1977; Snyder et al., 1978). 삉븳 꽭룷 떎뿕룞臾 닔以뿉꽌 鍮꾨쭔꽭룷쓽 븣윭吏 諛섏쓳쓣 뼲젣븳떎(Silwal et al., 2015).

쓳깋醫낆 뵾遺븫 以묒뿉꽌 媛옣 쟾씠꽦씠 겕怨 移섎즺븯湲 뼱졄떎(Paluncic et al., 2016). 븫 移섎즺 諛⑸쾿 以 븯굹뒗 븫꽭룷뿉꽌 꽭룷옄硫몄쓣 쑀룄빐 븫꽭룷 젣嫄고븯뒗 寃껋씠떎. 쓳깋醫낆쓣 솕븰슂踰뺤쑝濡 移섎즺븯뒗 寃껋 꽦怨쇨 醫뗭 븡뜲 洹 씠쑀뒗 븫꽭룷뿉꽌 꽭룷옄硫몄씠 쟻젅븯寃 씪뼱굹吏 븡湲 븣臾몄씠떎. 洹몃젃湲 븣臾몄뿉 꽭룷옄硫몄쓣 옒 씪쑝궗 닔 엳뒗 諛⑸쾿쓣 媛쒕컻븯뒗 寃껋 쓳깋醫 移섎즺뿉 留ㅼ슦 以묒슂븯떎(Lowe and Lin, 2000). 삉븳 꽭룷옄硫 珥됱쭊 뿬遺뒗 빆븫臾쇱쭏쓽 쑀슚꽦쓣 룊媛븯뒗 以묒슂븳 닔떒씠떎(Debatin, 2004).

꽭룷옄硫몄 쟻洹뱀쟻쑝濡 議곗젅릺뒗 꽭룷 二쎌쓬 怨쇱젙씠떎(Kerr et al., 1972). 씠 怨쇱젙 뿉꼫吏瑜 븘슂濡 븯硫 caspases 솢꽦솕瑜 닔諛섑븳떎(Elmore, 2007). Bcl-2 (B-cell lymphoma-2) 媛議 떒諛깆쭏 뼲젣꽦(Bcl-2, Bcl-XL (B-cell lymphoma-extra large) 洹몃━怨 Mcl-1 (myeloid cell leukemia-1)) 洹몃━怨 珥됱쭊꽦(Bid, Bax, and Bad) 꽭룷옄硫 遺꾩옄뱾쓣 룷븿븯硫 씠뱾 듅蹂꾪엳 caspase 솢꽦솕뿉 以묒슂븯떎(Cory and Adams, 2002). phosphatidylinositol 3-kinase (PI3K)/Akt/ mTOR 떊샇쟾떖 珥됱쭊꽦怨 뼲젣꽦 꽭룷옄硫 議곗젅 遺꾩옄씤 Bcl-2 媛議 떒諛깆쭏쓽 솢꽦솕瑜 議곗젅븯湲 븣臾몄뿉 PI3K/ Akt/mTOR 떊샇쟾떖 뼲젣臾쇱쭏 꽭룷옄硫몄쓣 議곗젅븷 닔 엳떎(Marone et al., 2009). PI3K/Akt 떊샇쟾떖 寃쎈줈뒗 꽭룷옄硫 빆꽦, 꽭룷깮議, 꽭룷 씠룞 벑쓣 議곗젅븳떎(Franke et al., 1997). 씠 寃쎈줈뒗 留롮 븫꽭룷 쟾씠꽦 쓳깋醫 꽭룷뿉꽌 솢꽦솕릺뼱 엳떎(Slipicevic et al., 2005). 뵲씪꽌 쓳깋醫 移섎즺젣 媛쒕컻쓽 二쇰맂 寃잛씠떎(Madhunapantula et al., 2011). PI3K 떊샇쟾떖 꽕듃썙겕뒗 뿬윭 媛吏 븯쐞 떊샇쟾떖 寃쎈줈媛 엳뒗뜲 洹 以 븯굹뒗 mTOR 솢꽦솕씠떎(Shaw and Cantley, 2006).

씠쟾 뿰援ъ뿉꽌 슦由щ뒗 븘뜲땶 쓳깋醫 꽭룷뿉꽌 caspase瑜 솢꽦솕떆耳 꽭룷옄硫몄쓣 쑀룄븿쓣 蹂댁떎(Silwal and Park, 2020). 씠 뿰援ъ뿉꽌뒗 caspase 솢꽦솕瑜 議곗젅븯뒗 Bcl 떒諛깆쭏怨 씠瑜 議곗젅븯뒗 PI3K/Akt/mTOR 떊샇쟾떖 寃쎈줈瑜 뿰援ы븯떎.

옱猷 諛 諛⑸쾿

옱猷

떎쓬쓽 옱猷뚮뱾 몴떆븳 쉶궗濡쒕꽣 援щℓ븯떎: adenine 援ъ엯泥섎뒗 Sigma-Aldrich, ST Louis, MO, USA; fetal bovine serum (FBS) 援ъ엯泥섎뒗 Gibco/Life Technologies; Dulbecc처s Modified Eagle Medium (DMEM) 援ъ엯泥섎뒗 Welgene, South Korea; anti-Akt, anti-phospho-Akt (Ser473 and Thr308), anti-phospho mTOR (Ser2448), anti-mTOR, anti-phospho-p70S6K (Thr389), anti-Bcl-2, anti-Bax antibodies 援ъ엯泥섎뒗 Cell Signaling Technology, Beverly, MA, USA; ECL chemiluminescence kit 援ъ엯泥섎뒗 Millipore, MA, USA; B16 melanoma cell line 援ъ엯泥섎뒗 American Type Culture Collection.

諛⑸쾿

꽭룷諛곗뼇: B16 melanoma 꽭룷뒗 10% FBS瑜 븿쑀븯뒗 DMEM뿉꽌 諛곗뼇븯떎. 怨듦린 CO2 냽룄瑜 5%濡 삩룄瑜 37꼦 쑀吏븯뒗 諛곗뼇湲곗뿉꽌 諛곗뼇븯떎. 꽭룷瑜 뿬윭 냽룄濡 븘뜲땶쓣 24떆媛 룞븞 泥섎━븯떎.

Western Blot 遺꾩꽍: 泥섎━媛 걹궃 꽭룷瑜 뼹쓬 긽깭뿉꽌 깋媛곷맂 PBS濡 꽭泥숉븯怨 슜빐 셿異⑹븸쓣 꽔怨 뼹쓬 쐞뿉꽌 30遺꾧컙 슜빐떆耳곕떎. 슜빐臾쇱쓣 紐⑥븘 12,000 rpm, 4꼦 議곌굔쑝濡 20遺꾧컙 썝떖遺꾨━ 븳 떎쓬 슜빐맂 臾쇱쭏쓣 紐⑥븘 룞웾쓽 4횞 SDS 깦뵆 셿異⑹븸쓣 꽔怨 5遺꾧컙 걪씤 떎쓬 SDS-PAGE瑜 닔뻾븯떎. SDS-PAGE濡 젮 긽뿉꽌 遺꾨━맂 떒諛깆쭏쓣 PVDF 硫ㅻ툕젅씤쑝濡 씠룞떆耳곕떎. 釉붾줈궧 슜븸 議곗꽦 5% 깉吏 遺꾩쑀 0.1% Tween 20쓣 븿쑀븯뒗 pH 8쓽 10 mM Tris 셿異⑹븸(TBS-T)쓣 궗슜븯떎. 4꼦뿉꽌 씪李 빆泥댁 떒諛깆쭏씠 삷寃⑥쭊 硫ㅻ툕젅씤쓣 諛ㅼ깉 諛섏쓳떆耳곕떎. TBS-T濡 硫ㅻ툕젅씤쓣 꽭泥숉븯怨 硫ㅻ툕젅씤쓣 5% 깉吏遺꾩쑀瑜 룷븿븯뒗 TBS-T뿉 삷寃⑥<怨 horseradish peroxidase 寃고빀맂 씠李 빆泥대 꽔怨 1떆媛 諛섏쓳떆耳곕떎. 꽭泥숉븳 떎쓬 chemiluminescence kit瑜 궗슜븯뿬 씪李 빆泥댁 諛섏쓳븯뒗 떒諛깆쭏쓣 寃異쒗븯떎. 냽룄遺꾩꽍 ImageJ瑜 궗슜븯떎.

寃 怨

븘뜲땶 泥섎━뒗 쓳깋醫 꽭룷 B16뿉꽌 Bax/Bcl2 鍮꾩쑉쓣 利앷떆궓떎

Bcl2 媛議 떒諛깆쭏 꽭룷옄硫멸낵 뿰愿꽦씠 넂 媛곸씤씠떎. 꽭룷옄硫 珥됱쭊꽦씤 Bax 떒諛깆쭏怨 뼲젣꽦씤 Bcl2쓽 鍮꾩쑉(Bax/Bcl2)씠 꽭룷옄硫 쑀룄뿉 以묒슂븯떎. 씠쟾 뿰援ъ뿉꽌 븘뜲땶 쓳깋醫 B16 꽭룷쓽 꽭룷옄硫몄쓣 씪쑝耳곌린 븣臾몄뿉 B16뿉 24떆媛 룞븞 뿬윭 냽룄쓽 븘뜲땶쓣 泥섎━븳 떎쓬 Bax/Bcl2 鍮꾩쑉쓣 痢≪젙븯떎. 븘뜲땶 泥섎━ 냽룄뿉 쓽議댁쟻쑝濡 Bax 떒諛깆쭏 諛쒗쁽 利앷븯怨, Bcl2 諛쒗쁽뼇 媛먯냼븯떎(Fig. 1A). 洹몄뿉 뵲씪 Bax/Bcl2 鍮꾩쑉 利앷븯떎(Fig. 1B). 씠윭븳 寃곌낵뒗 븘뜲땶씠 쓳깋醫 꽭룷 B16쓽 꽭룷옄硫몄쓣 씪쑝궎뒗 씠쑀뒗 Bax/Bcl2 鍮꾩쑉쓣 利앷떆궎湲 븣臾몄씪 寃껋씠씪 異붾줎븷 닔 엳떎.

Fig. 1. Adenine modulates Bax and Bcl-2 protein levels. (A) B16-F10 cells were exposed to various doses of adenine for 24 h in complete media. Cell lysates were used for Western blotting to detect indicated proteins. (B) Densitometry analysis of Bax and Bcl-2 done using ImageJ software and ratio of Bax and Bcl-2 was calculated. Data presented after normalizing the ratio with untreated control group. The data shown are representative of three independent experiments. Significant difference against control group is indicated as *P < 0.05.

븘뜲땶 泥섎━뒗 쓳깋醫 꽭룷 B16뿉꽌 Akt mTOR 떊샇쟾떖쓣 뼲젣븳떎

PI3K/Akt 떊샇쟾떖 寃쎈줈뒗 븫 諛쒖깮뿉꽌 以묒슂븳 뿭븷쓣 븯怨 엳떎. Akt 뼲젣뒗 꽭룷옄硫몄뿉 쓽븳 꽭룷 二쎌쓬쓣 珥됱쭊븯뿬 븫꽭룷쓽 꽦옣쓣 媛먯냼떆궓떎(Madhunapantula et al., 2011). 뵲씪꽌 B16 꽭룷뿉꽌 뿬윭 냽룄쓽 븘뜲땶쓣 24떆媛 泥섎━븯怨 Akt 떊샇쟾떖쓣 議곗궗븯떎(Fig. 2). 븘뜲땶 泥섎━ 냽룄뿉 쓽議댁쟻쑝濡 Akt 솢꽦솕 씤궛솕(Akt쓽 Ser 473怨 Thr308 쐞移섏쓽 씤궛솕)瑜 뼲젣븯떎. 씠윭븳 寃곌낵뒗 븘뜲땶씠 꽭룷옄硫몄쓣 씪쑝궎뒗 씠쑀뒗 Akt 씤궛솕瑜 뼲젣븯湲 븣臾몄씪 寃껋쑝濡 異붾줎븷 닔 엳떎.

Fig. 2. Adenine inhibits Akt/mTOR signaling. B16-F10 cells were exposed to various doses of adenine for 24 h in complete media and were used for Western blotting to detect phosphorylation of indicated proteins. The data shown are representative of three independent experiments.

삉븳 Akt뒗 mTOR瑜 씤궛솕떆耳 븫 吏꾪뻾쓣 珥됱쭊븯뒗 씪쓣 븳떎(He et al., 2021; Thorpe et al., 2015). mTOR媛 솢꽦솕릺硫 븫꽭룷쓽 꽦옣怨 遺꾩뿴씠 珥됱쭊릺怨, 꽭룷옄硫몄씠 뼲젣릺뼱 븫꽭룷媛 二쎌 紐삵븯寃 븳떎. 뵲씪꽌 mTOR뒗 븫쓽 移섎즺뿉 以묒슂븳 寃잛씠 릺怨 엳떎. 뵲씪꽌 븘뜲땶 泥섎━媛 mTOR쓽 솢꽦솕 씤궛솕(mTOR쓽 Ser2448 씤궛솕)瑜 뼲젣븯뒗 吏 議곗궗븯떎. 븘뜲땶 泥섎━ 냽룄뿉 쓽議댁쟻쑝濡 mTOR 솢꽦솕 씤궛솕瑜 뼲젣븯떎(Fig. 2). 씠윭븳 寃곌낵뒗 븘뜲땶씠 B16 꽭룷쓽 꽭룷옄硫몄쓣 씪쑝궎뒗 씠쑀뒗 mTOR 솢꽦솕瑜 뼲젣븯湲 븣臾몄씪 媛뒫꽦씠 엳떎.

怨 李

蹂 뿰援ъ뿉꽌뒗 븘뜲땶 泥섎━뿉 쓽븳 쓳깋醫 꽭룷 B16쓽 꽭룷옄硫 怨쇱젙뿉꽌 꽭룷옄硫 愿젴 遺꾩옄뱾쓣 痢≪젙븯떎. 꽭룷 궡 Bax/Bcl2 鍮꾩쑉씠 利앷븯怨 Akt mTOR쓽 솢꽦솕 씤궛솕瑜 뼲젣릺뿀떎. 꽭룷옄硫몄 Bcl-2 媛議 떒諛깆쭏뿉 쓽빐 議곗젅맂떎(Cory and Adams, 2002). 씠뱾 꽭룷옄硫몄쓣 떎뻾떆궎뒗 caspase瑜 솢꽦솕떆궓떎(Ola et al., 2011). 씠쟾 뿰援ъ뿉꽌 븘뜲땶 caspase 솢꽦솕瑜 씪쑝耳 꽭룷瑜 꽭룷옄硫몃줈 二쎄쾶 븯뒗 쁽긽쓣 蹂닿퀬븯떎(Silwal and Park, 2020). 蹂 뿰援ъ뿉꽌 븘뜲땶 泥섎━뒗 꽭룷옄硫 珥됱쭊꽦 遺꾩옄 Bax瑜 利앷떆궎怨 꽭룷옄硫 뼲젣꽦 Bcl-2瑜 媛먯냼떆궡쓣 愿李고븯떎. 利, 븘뜲땶 泥섎━媛 caspase瑜 솢꽦솕떆궎뒗 씠쑀뒗 Bax/Bcl2 鍮꾩쑉쓣 利앷떆궎湲 븣臾몄엫쓣 蹂댁뿬二쇨퀬 엳떎. 씠윭븳 寃곌낵뒗 留롮 쓳깋醫 꽭룷뿉꽌 Bax/Bcl-2 鍮꾩쑉 媛먯냼뒗 븫 吏꾪뻾怨 뿰愿 엳떎뒗 蹂닿퀬 씪移섑븳떎(Leiter et al., 2000).

PI3K/Akt 떊샇쟾떖 寃쎈줈뒗 꽭룷쓽 利앹떇怨 깮議대퓧 븘땲씪 쓳깋醫낆쓣 룷븿븯뒗 븫꽭룷 쟾씠뿉 以묒슂븳 뿭븷쓣 븳떎(Slipicevic et al., 2005). Akt쓽 넂 씤궛솕 젙룄뒗 쓳깋醫낆뿉꽌 愿李곕릺硫 솚옄쓽 깮議 젙룄뿉 醫뗭 븡떎(Dai et al., 2005). Akt 솢꽦솕뒗 꽭룷옄硫몄쓣 珥됱쭊븯뒗 遺꾩옄뱾쓣 利앷떆궎怨 뼲젣븯뒗 遺꾩옄뱾쓣 媛먯냼떆궓떎(Franke et al., 1997). 洹몃윭誘濡 븫 移섎즺젣 媛쒕컻 뿰援щ뒗 PI3K/Akt 떊샇쟾떖 寃쎈줈(Deng et al., 2012) 洹몄쓽 븯쐞 몴쟻씤 mTOR뿉 以묒젏쓣 몢怨 엳떎(Shaw and Cantley, 2006). 꽭룷옄硫몄뿉 以묒슂븳 Bcl-2 媛議 떒諛깆쭏 뼇 議곗젅 PI3K/Akt 떊샇쟾떖뿉 쓽議댄븳떎. 利, PI3K/Akt 떊샇쟾떖 Bax瑜 媛먯냼떆궎怨 Bcl-2뒗 利앷떆耳 꽭룷옄硫몄쓣 뼲젣븳떎. 蹂 뿰援ъ뿉꽌 쓳깋醫 꽭룷뿉 븘뜲땶쓣 泥섎━븯땲 Bax/Bcl-2 鍮꾩쑉씠 利앷븯떎. 씠윭븳 寃곌낵뱾 븘뜲땶씠 PI3K/Akt 떊샇쟾떖 寃쎈줈瑜 뼲젣븯뿬 Bax/Bcl-2 鍮꾩쑉쓣 利앷떆耳 꽭룷옄硫몄쓣 利앷떆耳곕떎怨 깮媛곹븷 닔 엳떎.

寃곕줎쟻쑝濡 蹂 뿰援щ뒗 븘뜲땶씠 쓳깋醫 B16 꽭룷瑜 꽭룷옄硫몄쓣 넻빐 二쎌씠뒗 湲곗쟾 븘뜲땶씠 PI3K/Akt 떊샇쟾떖쓣 뼲젣븿쑝濡쒖뜥 Bax/Bcl-2 鍮꾩쑉쓣 利앷떆궎怨 mTOR 솢꽦쓣 뼲젣븯湲 븣臾몄씠씪怨 異붿륫븷 닔 엳떎. 씠 뿰援ш 빆븫젣 媛쒕컻뿉 湲곗뿬븷 닔 엳湲곕 諛붾떎.

ACKNOWLEDGEMENT

This work was financially supported by research funds of Chungnam National University.

CONFLICT OF INTEREST

The author has no conflict of interest with regards to this study.

References
  1. Avila MA, Garcia-Trevijano ER, Lu SC, Corrales FJ, Mato JM. Methylthioadenosine. Int J Biochem Cell Biol. 2004. 36: 2125-2130.
    Pubmed CrossRef
  2. Cory S, Adams JM. The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer. 2002. 2: 647-656.
    Pubmed CrossRef
  3. Dai DL, Martinka M, Li G. Prognostic significance of activated Akt expression in melanoma: a clinicopathologic study of 292 cases. J Clin Oncol. 2005. 23: 1473-1482.
    Pubmed CrossRef
  4. Debatin KM. Apoptosis pathways in cancer and cancer therapy. Cancer Immunol Immunother. 2004. 53: 153-159.
    Pubmed CrossRef
  5. Deng W, Gopal YN, Scott A, Chen G, Woodman SE, Davies MA. Role and therapeutic potential of PI3K-mTOR signaling in de novo resistance to BRAF inhibition. Pigment Cell Melanoma Res. 2012. 25: 248-258.
    Pubmed CrossRef
  6. Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007. 35: 495-516.
    Pubmed KoreaMed CrossRef
  7. Franke TF, Kaplan DR, Cantley LC. PI3K: downstream AKTion blocks apoptosis. Cell. 1997. 88: 435-437.
    Pubmed CrossRef
  8. He Y, Sun MM, Zhang GG, Yang J, Chen KS, Xu WW, Li B. Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduct Target Ther. 2021. 6: 425.
    Pubmed KoreaMed CrossRef
  9. Hershfield MS, Snyder FF, Seegmiller JE. Adenine and adenosine are toxic to human lymphoblast mutants defective in purine salvage enzymes. Science. 1977. 197: 1284-1287.
    Pubmed CrossRef
  10. Kamatani N, Carson DA. Dependence of adenine production upon polyamine synthesis in cultured human lymphoblasts. Biochim Biophys Acta. 1981. 675: 344-350.
    CrossRef
  11. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972. 26: 239-257.
    Pubmed KoreaMed CrossRef
  12. Leiter U, Schmid RM, Kaskel P, Peter RU, Krahn G. Antiapoptotic bcl-2 and bcl-xL in advanced malignant melanoma. Arch Dermatol Res. 2000. 292: 225-232.
    Pubmed CrossRef
  13. Lowe SW, Lin AW. Apoptosis in cancer. Carcinogenesis. 2000. 21: 485-495.
    Pubmed CrossRef
  14. Madhunapantula SV, Mosca PJ, Robertson GP. The Akt signaling pathway: an emerging therapeutic target in malignant melanoma. Cancer Biol Ther. 2011. 12: 1032-1049.
    Pubmed KoreaMed CrossRef
  15. Marone R, Erhart D, Mertz AC, Bohnacker T, Schnell C, Cmiljanovic V, Stauffer F, Garcia-Echeverria C, Giese B, Maira SM, Wymann MP. Targeting melanoma with dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors. Mol Cancer Res. 2009. 7: 601-613.
    Pubmed CrossRef
  16. Ola MS, Nawaz M, Ahsan H. Role of Bcl-2 family proteins and caspases in the regulation of apoptosis. Mol Cell Biochem. 2011. 351: 41-58.
    Pubmed CrossRef
  17. Paluncic J, Kovacevic Z, Jansson PJ, Kalinowski D, Merlot AM, Huang ML, Lok HC, Sahni S, Lane DJ, Richardson DR. Roads to melanoma: Key pathways and emerging players in melanoma progression and oncogenic signaling. Biochim Biophys Acta. 2016. 1863: 770-784.
    Pubmed CrossRef
  18. Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature. 2006. 441: 424-430.
    Pubmed CrossRef
  19. Silwal P, Shin K, Choi S, Kang SW, Park JB, Lee HJ, Koo SJ, Chung KH, Namgung U, Lim K, Heo JY, Park JI, Park SK. Adenine suppresses IgE-mediated mast cell activation. Mol Immunol. 2015. 65: 242-249.
    Pubmed CrossRef
  20. Silwal P, Park SK. Adenine Inhibits B16-F10 Melanoma Cell Proliferation. Biomedical Science Letters. 2020. 26: 179-185.
    CrossRef
  21. Simon ER, Chapman RG, Finch CA. Adenine in red cell preservation. J Clin Invest. 1962. 41: 351-359.
    Pubmed KoreaMed CrossRef
  22. Slipicevic A, Holm R, Nguyen MT, Bohler PJ, Davidson B, Florenes VA. Expression of activated Akt and PTEN in malignant melanomas: relationship with clinical outcome. Am J Clin Pathol. 2005. 124: 528-536.
    Pubmed CrossRef
  23. Snyder FF, Hershfield MS, Seegmiller JE. Cytotoxic and metabolic effects of adenosine and adenine on human lymphoblasts. Cancer Res. 1978. 38: 2357-2362.
  24. Thorpe LM, Yuzugullu H, Zhao JJ. PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer. 2015. 15: 7-24.
    Pubmed KoreaMed CrossRef
  25. Watanabe S, Yoshimi Y, Ikekita M. Neuroprotective effect of adenine on purkinje cell survival in rat cerebellar primary cultures. J Neurosci Res. 2003. 74: 754-759.
    Pubmed CrossRef