Abstract B061: Effect of artonin E on apoptosis cell death induction in colon cancer cell

Abstract

Colon cancer is the most common cause of cancer death in both men and women around the world. The three human RAS genes (KRAS, NRAS and HRAS) are the most frequently mutated oncogenes in human cancer including pancreatic, lung and colon cancers. In particular, KRAS mutated gene prevalently found in pancreas, lung and colon cancer [1]. In colorectal cancer patients, approximately 35-45% mutated KRAS oncogene was reported. The downstream of KRAS associated with survival signaling pathways including Raf/Mek/MAPK and PI3K/Akt [2]. Normally, cancer cell escape death induction by upregulation of Raf/Mek/MAPK and PI3K/Akt activity. Thus, inhibition of Raf/Mek/MAPK and PI3K/Akt signaling pathway is necessary. Nowadays, treatment of colon cancer is quite limited due to the high cost and side effects, therefore, bioactive compound therapy might be the choice for development of colon cancer treatment. In this study, we investigate the effect of artonin E on apoptosis induction in colon cancer HCT116 cells. Nuclear morphological changes and the loss of mitochondrial membrane potential, characteristics of apoptosis induction were determined by Hoechst 33342 staining and JC-1 staining, respectively. Mediator proteins that associated with apoptosis induction and signaling molecules were determined by Western blot analysis. Our results indicated that artonin E induced apoptotic bodies and loss of mitochondrial membrane potential in HCT116 treated cells. In addition, artonin E showed upregulation of cleave-caspase-7 (active form) and cleave-PARP (inactive form), mediator of apoptosis induction, in HCT116 cells. Moreover, artonin E reduced Akt and increased p-ERK1/2 expression in HCT116 cells. This data correlated with previous study by Tangchirakhaphan et al and Bee-Jen Tan et al, that ERK1/2 could activate caspase and pro-apoptotic protein in Bcl-2 family. Moreover, ERK1/2 could deactivate Akt signaling pathway leading to apoptosis induction [3,4]. Our study indicated that artonin E induced apoptosis cell death through p-ERK1/2 upregulation and may be used as a potential therapeutic candidate in the future. Keywords: Artonin E, Apoptosis, Colon cancer, KRAS [1] Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. Drugging the undruggable RAS: Mission possible? Nat Rev Drug Discov. 2014;13(11):828-51. [2] Eser S, Schnieke A, Schneider G, Saur D. Oncogenic KRAS signalling in pancreatic cancer. Br J Cancer. 2014;111(5):817-22. [3] Tangchirakhaphan S, Innajak S, Nilwarangkoon S, Tanjapatkul N, Mahabusrakum W, Watanapokasin R. Mechanism of apoptosis induction associated with ERK1/2 upregulation via goniothalamin in melanoma cells. Exp Ther Med. 2018;15(3):3052-8. [4] Tan BJ, Chiu GN. Role of oxidative stress, endoplasmic reticulum stress and ERK activation in triptolide-induced apoptosis. Int J Oncol. 2013;42(5):1605-12. Citation Format: Supichaya Nimnuan-ngam, Kanyaluck Yangnok, Sukanda Innajak, Ramida Watanapokasin. Effect of artonin E on apoptosis cell death induction in colon cancer cell [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B061.

Anticancer mechanism of artonin E and related prenylated flavonoids from the medicinal plant Artocarpus elasticus

“…The compound downregulated DR5 while it up-regulated the other major regulator of TRAIL-induced apoptosis called cFLIP (cellular FADD-like-IL-1beta-converting enzymeinhibitory protein) on LoVo cells (Sophonnithiprasert et al 2019). Remarkably, Art-E can trigger cell arrest (S phase) and a massive mitochondria-dependent apoptosis in SKOV-3 ovarian cancer cells (Rahman et al 2016) and in HCT116 colon cancer cells, Art-E induced apoptosis through upregulation of p-ERK1/2 (Nimnuan-ngam et al 2020).…”