Aspirin exerts high anti-cancer activity in PIK3CA-mutant colon cancer cells

Mancang Gu; Reiko Nishihara; Yang Chen; Wanwan Li; Yan Shi; Yohei Masugi; Tsuyoshi Hamada; Keisuke Kosumi; Li Liu; Annacarolina da Silva; Jonathan A Nowak; Tyler Twombly; Chunxia Du; Hideo Koh; Wenbin Li; Jeffrey A Meyerhardt; Brian M Wolpin; Marios Giannakis; Andrew J Aguirre; Adam J Bass; David A Drew; Andrew T Chan; Charles S Fuchs; Zhi Rong Qian; Shuji Ogino

doi:10.18632/oncotarget.20972

Aspirin exerts high anti-cancer activity in PIK3CA-mutant colon cancer cells

Oncotarget. 2017 Sep 18;8(50):87379-87389. doi: 10.18632/oncotarget.20972. eCollection 2017 Oct 20.

Authors

Mancang Gu^{1

2}, Reiko Nishihara^{1

3

4

5

6}, Yang Chen^{1

7}, Wanwan Li¹, Yan Shi^{1

7}, Yohei Masugi¹, Tsuyoshi Hamada¹, Keisuke Kosumi¹, Li Liu^{1

3}, Annacarolina da Silva¹, Jonathan A Nowak⁶, Tyler Twombly¹, Chunxia Du¹, Hideo Koh¹, Wenbin Li¹, Jeffrey A Meyerhardt⁸, Brian M Wolpin⁸, Marios Giannakis⁸, Andrew J Aguirre⁸, Adam J Bass^{8

9

10}, David A Drew^{11

12}, Andrew T Chan^{11

12}, Charles S Fuchs^#^{13

14

15}, Zhi Rong Qian^#^{1

6}, Shuji Ogino^#^{1

4

6}

Affiliations

¹ Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
² College of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, P.R. China.
³ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁵ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁶ Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁷ Medical Oncology Department 2, Chinese People's Liberation Army General Hospital, Beijing, P.R. China.
⁸ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
⁹ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁰ Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹¹ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹² Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA.
¹³ Yale Cancer Center, New Haven, CT, USA.
¹⁴ Department of Medicine, Yale School of Medicine, New Haven, CT, USA.
¹⁵ Smilow Cancer Hospital, New Haven, CT, USA.

^# Contributed equally.

Abstract

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.

Keywords: NSAID; PI3K; anti-tumor effect; colorectal cancer; isogenic cell model.

Abstract

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