Oncogenic H‐Ras, FK228, and exogenous H₂O₂ cooperatively activated the erk pathway in selective induction of human urinary bladder cancer j82 cell death

Abstract

More than 35% of human urinary bladder cancers involve oncogenic H-Ras activation. The goal of this study was to investigate the role of the ERK pathway in mediating apoptotic signals induced by oncogenic H-Ras, FK228 treatment, and exogenous H(2) O(2) treatment to increase Nox-1 elevation, leading to production of intracellular reactive oxygen species (ROS) for inducing apoptosis in human bladder cancer J82 cells. Our study revealed that FK228 combined with exogenous H(2)O(2) cooperatively induced activation of Mek1/2 and Erk1/2 to increase Nox-1 elevation, intracellular ROS production, caspase activation, and cell death. Expression of oncogenic H-Ras significantly increased these FK228- and exogenous H(2)O(2)-induced effects. Oncogenic H-Ras-increased cell susceptibility to FK228 could be alternately achieved by additional treatment with exogenous H(2)O(2). Hence, combined use of FK228 with ROS-generating agents may apply to therapeutic strategies to preferentially kill malignant cells with or without oncogenic H-Ras activation.

Ras and Rac1, Frequently Mutated in Melanomas, Are Activated by Superoxide Anion, Modulate Dnmt1 Level and Are Causally Related to Melanocyte Malignant Transformation

“…Normally, cell response to pathological ROS levels activates numerous intracellular signaling pathways, which in turn regulate transcriptional changes that allow cells to respond appropriately to new environment. Several authors have shown that activation of Ras signaling pathway leads to increased intracellular ROS levels in different cell lines, such as keratinocytes and epithelial cells [44], [45], [46]. Although the above studies implicate Ras signal transduction in the generation and regulation of intracellular superoxide anion levels, there are few evidences that Ras can be also activated by ROS [47], [48], [49].…”

HRASis silenced by two neighboring G-quadruplexes and activated by MAZ, a zinc-finger transcription factor with DNA unfolding property

“…Given their critical role in transcription regulation, the two neighboring G-quadruplexes can be targeted by small ligands in order to downregulate HRAS : an oncogene playing a key role in the pathogenesis of urinary bladder cancer (5,6,33,34). These molecules should bind preferentially G4-DNA instead of B-DNA, and consequently repress transcription by increasing the stability of the G-quadruplexes.…”

The Interplay between ROS and Ras GTPases: Physiological and Pathological Implications

“…Oncogenic H-Ras-increased susceptibility to FK228 could be alternatively achieved by additional treatment with exogenous H 2 O 2 . These findings have important and useful implications as combined use of HDACIs with ROS-generating agents may apply to therapeutic strategies to preferentially kill malignant cells with or without oncogenic H-Ras activation [91]. …”