Serum deprivation primes cancer cells to adapt and survive oxidative stress

Abstract

Inadequate nutrient intake, a survival benchmark in cancer cells, leads to oxidative stress (OS) disrupting homeostasis, activating signaling, and altering metabolism. As reactive oxygen species (ROS) increase, oxidative stressors activate mechanisms allowing cancer cells to adapt and survive. Our data suggests that nutrient‐deprived cancer cells tolerate OS. Moreover, a quiescent phenotype along with nuclear factor‐kappaB (NF‐κB) signaling may synergistically protect tumor cells from OS induced by nutrient deprivation. In DU145 prostate cancer cell line, we observed that serum‐deprived cells maintained viability after exposure to H2O2 and transitioned to a quiescent phenotype via up‐regulated quiescent markers. Additionally, we transiently silenced NF‐κB (RelA/p65) via siRNA, and demonstrated the percentage of total apoptosis in DU145 cells significantly increased in serum‐deprived cells exposed to H2O2. Furthermore, we observed that inhibition of quiescence significantly reduced NF‐κB‐mediated cell survival in response to OS using two quiescence inhibitors targeting Mirk/Dyrk1b kinase (quiescence inducer), AZ191 and NCGC00185981‐05/ML195; concomitantly, a distinct NF‐κB nuclear localization was not observed. It is unclear how prostate cancer cells adapt and survive oxidative stress; however, we hypothesize nutrient deprivation primes cancer cells for OS cell survival, concurrent with a transition to a quiescent phenotype and NF‐κB signaling. Support or Funding Information These studies were supported by the NIH/NIGMS/RISE #5R25GM060414‐15 and NIH/NIHMD/RCMI #5G12MD007590.