Abstract 5993: Inhibition of isorhapontigenin on migration and invasion of bladder cancer cells depends on Sestrin 2 and Beclin 1

Abstract

Abstract Bladder cancer is the fourth most common cancer in men in the United States. It has been reported that about 83,730 new cases of bladder cancer and 17,200 deaths from bladder cancer occurred in 2021. Therefore, the discovery of new alternative medication becomes extremely important for reduction of cancer mortality. Isorhapontigenin (ISO), a phytopolyphenol, is derivative stilbene isolated from the Chinese herb Gnetum cleistostachyum. It has been reported that ISO exhibits multiple anticancer activities in human high grade invasive bladder cancer cells. Our previous study has demonstrated that ISO treatment increased methyltransferase 14, N6-adenosine-methyltransferase subunit (METTL14), subsequently decreased vimentin, a key member of epithelial mesenchymal transition (EMT), resulting in reduced invasion of bladder cancer T24T cells. Autophagy maintains normal cell homeostasis through the removal of oncogenic protein substrates, toxic unfolded proteins and damaged organelles. Tumor-promoting or tumor-inhibiting functions of autophagy depends on the cancer type and stage. Sestrin 2, a member of stress-inducible protein family which is essential for maintaining metabolic homeostasis, is involved in the autophagy initiation. Beclin 1, a key autophagy regulator, is involved in multiple stages of autophagy. The present study investigated the mechanisms of ISO-inhibited migration and invasion in bladder cancer cells by focusing on Sestrin 2 and Beclin 1 pathways. Our results showed that ISO treatment in bladder cancer T24T decreased both migration and invasion as assessed by using transwell assays. However, in T24T cells with Sestrin 2 knockdown or Beclin 1 knockdown ISO lost the inhibitory effect on migration and invasion. The results from immunoblotting analysis showed that knockdown of Sestrin 2 or Beclin 1 increased N-cadherin and vimentin, two important members of EMT. While treatment with ISO in T24T wildtype cells decreased N-cadherin and vimentin, ISO did not have any effect on N-cadherin or vimentin in T24T cells with Sestrin 2 or Beclin 1 knockdown. Furthermore, ISO treatment reduced protein levels of Atg7 and Bcl-2 in T24T wildtype cells. ISO failed to decrease Atg7 and Bcl-2 in those T24T cells with Sestrin 2 or Beclin 1 knockdown. The present study suggested that ISO inhibits migration and invasion of bladder cancer cells and the inhibition of ISO is dependent on Sestrin 2 and Beclin 1, and induction of autophagy by ISO reduces migration and invasion of bladder cancer cells. The present study provides evidence that ISO can be a candidate of chemotherapy. Citation Format: Zhuo Zhang, Jingxia Li, Huailu Tu, Max Costa. Inhibition of isorhapontigenin on migration and invasion of bladder cancer cells depends on Sestrin 2 and Beclin 1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5993.