Abstract C058: Vitamin C preferentially induces growth inhibition and cell death in KRAS G12D-mutant pancreatic cancer cells

Abstract

Abstract Vitamin C (L-Ascorbic acid, VC), an anti-oxidant has been studied as the possible potent chemotherapeutic drug in various cancers including colorectal cancer, breast cancer, ovarian cancer, prostate cancer and lung cancer. In particular, it is recently reported that VC kills efficiently colorectal cancer cells with KRAS or BRAF mutations. Give fact that pancreatic cancer has high frequency of KRAS mutation rate and is one of the most aggressive and lethal cancers with lack of effective therapy targeting the KRAS mutations, we would like to investigate whether VC effectively kills pancreatic cancer cells with various types of KRAS mutation. We first tested cytotoxicity and cell growth inhibition effect of VC on pancreatic cancer cell lines. In growth inhibition and colony formation assay, VC showed differential effect on cell growth and colony formation according to the KRAS genotypes. Treatment of the pancreatic cancer cell lines harboring KRAS G12D mutation with VC resulted in marked decrease of cell survival and colony formation, while same treatment of the cell lines with other KRAS mutations or wild type had no growth inhibitory effect. Interestingly, although there was no dramatic difference in well-known VC transporters, Glut1 expression according to the KRAS genotypes, sodium-dependent vitamin c transporter 2 (SVCT2) expression was relatively lower in KRAS G12D-mutant pancreatic cancer cells than other cells. To study possible mechanisms of VC-induced growth inhibition and cell death, we also tested whether glycolysis was inhibited or not though extracellular acidification rate (ECAR) measurement. After 1mM VC injection, ECAR decreased dramatically in KRAS G12D-mutant pancreatic cancer cells compared to the other genotypes. In cell cycle phospho-antibody array analysis, the results indicated that VC significantly increased the expression of DNA damage-associated proteins. Finally, we also found that cell death measured by apoptosis increased in KRAS G12D-mutant pancreatic cancer cells with VC through annexin V-PI staining FACS analysis. In conclusion, we showed VC selectively induces the apoptosis and cell growth inhibition in KRAS G12D-mutant pancreatic cancer cells than other KRAS mutations by inhibition of glycolysis and induction of DNA damage-associated proteins. Our findings suggest that VC is needed to further investigate as the potential novel agent with cytotoxic chemotherapies for the treatment of pancreatic cancer. Citation Format: Hye-Lim Jang, Jung Yong Hong, Seung Tae Kim, Jeeyun Lee, Se Hoon Park, Young Suk Park, Ho Yeong Lim, Won Ki Kang, Joon Oh Park. Vitamin C preferentially induces growth inhibition and cell death in KRAS G12D-mutant pancreatic cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C058. doi:10.1158/1535-7163.TARG-19-C058