Aspirin exerts high anti-cancer activity in PIK3CA-mutant colon cancer cells.
Aspirin exerts high anti-cancer activity in PIK3CA-mutant colon cancer cells.
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DOI：
10.18632/oncotarget.20972
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发表时间：
2017-10-20
期刊：
影响因子：
--
通讯作者：
Ogino S
中科院分区：
文献类型：
--
作者：
Gu M;Nishihara R;Chen Y;Li W;Shi Y;Masugi Y;Hamada T;Kosumi K;Liu L;da Silva A;Nowak JA;Twombly T;Du C;Koh H;Li W;Meyerhardt JA;Wolpin BM;Giannakis M;Aguirre AJ;Bass AJ;Drew DA;Chan AT;Fuchs CS;Qian ZR;Ogino S
有证据表明，非类固醇抗炎药阿司匹林(乙酰水杨酸)可以提高PIK3CA突变结直肠癌患者的生存率，但对PIK3CA野生型结直肠癌患者没有改善作用。然而，阿司匹林是否直接影响PIK3CA突变的结肠癌细胞的活力还知之甚少。我们进行了体外实验，以验证我们的假设，即阿司匹林对PIK3CA突变的结肠癌细胞的抗增殖活性可能强于PIK3CA野生型结肠癌细胞。我们测定了生理浓度的阿司匹林在7个PIK3CA突变株和6个PIK3CA野生型人结肠癌细胞系中的抗增殖作用。阿司匹林作用后，检测结肠癌细胞的凋亡指数和细胞周期时相。此外，阿司匹林在亲代SW48细胞和带有单独敲入PIK3CA突变的亲本SW48细胞和SW48细胞克隆中进行了检测，其中c.3140A和gt；G(p.H1047R)或c.1633G>；A(p.E545K)。阿司匹林作用48小时和72小时后，PIK3CA突变细胞的细胞活力比野生型PIK3CA细胞的细胞活力下降幅度更大。阿司匹林处理后PIK3CA突变细胞的细胞凋亡率和G0/G1期停滞比例也高于野生型PIK3CA细胞。与野生型对照相比，阿司匹林处理携带PIK3CA突变的同基因SW48细胞，无论是c.3140A>；G(p.H1047R)还是c.1633G>；A(p.E545K)，导致细胞活力更显著的丧失。我们的研究结果表明，在PIK3CA突变的结肠癌细胞中，阿司匹林导致细胞周期停滞，诱导细胞凋亡，并导致细胞活力丧失的程度比PIK3CA-野生型结肠癌细胞更严重。这些发现支持使用阿司匹林治疗PIK3CA突变结肠癌患者。
Evidence suggests that nonsteroidal anti-inflammatory drug aspirin (acetylsalicylic acid) may improve patient survival in PIK3CA-mutant colorectal carcinoma, but not in PIK3CA-wild-type carcinoma. However, whether aspirin directly influences the viability of PIK3CA-mutant colon cancer cells is poorly understood. We conducted in vitro experiments to test our hypothesis that the anti-proliferative activity of aspirin might be stronger for PIK3CA-mutant colon cancer cells than for PIK3CA-wild-type colon cancer cells. We measured the anti-proliferative effect of aspirin at physiologic concentrations in seven PIK3CA-mutant and six PIK3CA-wild-type human colon cancer cell lines. After exposure to aspirin, the apoptotic index and cell cycle phase of colon cancer cells were assessed. In addition, the effect of aspirin was examined in parental SW48 cells and SW48 cell clones with individual knock-in PIK3CA mutations of either c.3140A>G (p.H1047R) or c.1633G>A (p.E545K). Aspirin induced greater dose-dependent loss of cell viability in PIK3CA-mutant cells than in PIK3CA-wild-type cells after treatment for 48 and 72 hours. Aspirin treatment also led to higher proportions of apoptotic cells and G0/G1 phase arrest in PIK3CA-mutant cells than in PIK3CA-wild-type cells. Aspirin treatment of isogenic SW48 cells carrying a PIK3CA mutation, either c.3140A>G (p.H1047R) or c.1633G>A (p. E545K), resulted in a more significant loss of cell viability compared to wild-type controls. Our findings indicate that aspirin causes cell cycle arrest, induces apoptosis, and leads to loss of cell viability more profoundly in PIK3CA-mutated colon cancer cells than in PIK3CA-wild-type colon cancer cells. These findings support the use of aspirin to treat patients with PIK3CA-mutant colon cancer.
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影响因子：
29.4
作者：
Cao Y;Nishihara R;Qian ZR;Song M;Mima K;Inamura K;Nowak JA;Drew DA;Lochhead P;Nosho K;Morikawa T;Zhang X;Wu K;Wang M;Garrett WS;Giovannucci EL;Fuchs CS;Chan AT;Ogino S
通讯作者：
Ogino S
影响因子：
39.2
作者：
Dehmer, Steven P.;Maciosek, Michael V.;Whitlock, Evelyn P.
通讯作者：
Whitlock, Evelyn P.
影响因子：
4.2
作者：
Claudius, Ann-Katrin;Kankipati, Chandra S.;Nicholl, Iain D.
通讯作者：
Nicholl, Iain D.
影响因子：
2.2
作者：
Coyle C;Cafferty FH;Rowley S;MacKenzie M;Berkman L;Gupta S;Pramesh CS;Gilbert D;Kynaston H;Cameron D;Wilson RH;Ring A;Langley RE;Add-Aspirin investigators
通讯作者：
Add-Aspirin investigators
影响因子：
11.2
作者：
Isakoff, SJ;Engelman, JA;Brugge, JS
通讯作者：
Brugge, JS