Pyridoxine enhances chemo-responsiveness of breast cancer stem cells via redox reconditioning

Shruti Banerjee, Shravanti Mukherjee, Apoorva Bhattacharya, Udit Basak, Sourio Chakraborty, Swastika Paul, Poulami Khan, Kuladip Jana, Tapas K. Hazra, Tanya Das

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

A plethora of molecular strategies are employed by breast cancer stem cells (bCSCs) to evade chemotherapy-induced death signals, redox modulation being a crucial factor among those. Here, we observed that bCSCs are resistant to DNA damage and generate low ROS upon doxorubicin (Dox) treatment. Further exploration revealed inherently high NEIL2, a base excision repair (BER) enzyme that plays a key regulatory role in repairing DNA damage, in bCSCs. However, its role in modulating the redox status of bCSCs remains unexplored. In addition, Dox not only upregulates NEIL2 in bCSCs at both transcriptional and translational levels but also declines p300-induced acetylation thus activating NEIL2 and providing a protective effect against the stress inflicted by the genotoxic drug. However, when the redox status of bCSCs is altered by inducing high ROS, apoptosis of the resistant population is accomplished. Subsequently, when NEIL2 is suppressed in bCSCs, chemo-sensitization of the resistant population is enabled by redox reconditioning via impaired DNA repair. This signifies a possibility of therapeutically disrupting the redox balance in bCSCs to enhance their chemo-responsiveness. Our search for an inhibitor of NEIL2 revealed that vitamin B6, i.e., pyridoxine (PN), hinders NEIL2-mediated transcription-coupled repair process by not only decreasing NEIL2 expression but also inhibiting its association with RNA Pol II, thus stimulating DNA damage and triggering ROS. As a consequence of altered redox regulation, bCSCs become susceptible towards Dox, which then induces apoptosis via caspase cascade. These findings signify that PN enhances chemo-responsiveness of bCSCs via redox reconditioning.

Original languageEnglish (US)
Pages (from-to)152-165
Number of pages14
JournalFree Radical Biology and Medicine
Volume152
DOIs
StatePublished - May 20 2020

Keywords

  • DNA damage
  • NEIL2
  • Pyridoxine
  • ROS
  • bCSCs

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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