Graphene oxide-chloroquine conjugate induces DNA damage in A549 lung cancer cells through autophagy modulation
Braham Dutt Arya1,2,3, Sandeep Mittal2,4, Prachi Joshi1
1CSIR-National Physical Laboratory, Dr K. S. Krishanan Marg, New Delhi-12, India.
Abstract:
Autophagy is a highly regulated catabolic process by which unnecessary, dysfunctional, or damaged proteins and other cellular components are degraded and recycled to promote cellular differentiation, survival, and development. In response to endogenous or exogenous stresses, cancer cells use autophagy pathways for survival through activation of complex DNA damage repair (DDR) mechanisms. In the present study, we demonstrated the genotoxicity induced in A549 lung cancer cells by exposure to the GO-Chl nanoconjugate and elucidated the role of autophagy modulation in harnessing the DNA-damage response. GO-Chl causes loss of plasma membrane integrity, cell cycle arrest, and significant genotoxicity in A549 cells. Further, elevated expression of key autophagy proteins beclin-1, ATG-7, LC-3-I/II, and SQSTM1/p62 reveal that inhibition of autophagy plays a crucial role in regulating DDR capabilities of cancer cells. The results indicate that the interplay between DDR and autophagy pathways may open new paradigms for developing effective combinatorial nanoscale drug systems against multidrug-resistance cancers.
Insights
This study shows that a GO-Chl nanoconjugate induces genotoxicity in lung cancer cells. Autophagy inhibition is key to regulating DNA damage repair, offering new cancer therapy strategies.
Area of Science:
- Cell Biology
- Nanomedicine
- Cancer Research
Background:
- Autophagy is a cellular process crucial for survival and development.
- Cancer cells exploit autophagy for survival, often activating DNA damage repair (DDR) mechanisms.
- Nanoconjugates offer potential for targeted cancer therapies.
Purpose of the Study:
- To investigate the genotoxicity of the GO-Chl nanoconjugate in A549 lung cancer cells.
- To elucidate the role of autophagy modulation in the DNA-damage response within these cancer cells.
- To explore the interplay between DDR and autophagy for novel cancer treatment strategies.
Main Methods:
- Exposure of A549 lung cancer cells to the GO-Chl nanoconjugate.
- Assessment of genotoxicity, plasma membrane integrity, and cell cycle arrest.
- Analysis of key autophagy protein expression (beclin-1, ATG-7, LC-3-I/II, SQSTM1/p62).
Main Results:
- GO-Chl nanoconjugate induced significant genotoxicity, loss of plasma membrane integrity, and cell cycle arrest in A549 cells.
- Elevated expression of autophagy proteins (beclin-1, ATG-7, LC-3-I/II, SQSTM1/p62) was observed.
- Autophagy inhibition was found to be crucial in regulating the DNA-damage response.
Conclusions:
- The GO-Chl nanoconjugate exhibits genotoxic effects on lung cancer cells.
- Autophagy plays a critical role in modulating the DNA damage response in cancer.
- Targeting the interplay between autophagy and DDR presents a promising avenue for developing combinatorial nanoscale drug systems against multidrug-resistant cancers.
