Mechanisms of therapy induced senescence reversal

March 22, 2021

Dr. Salunkhe is working as a postdoctoral researcher with Dr. Patrick Sung at the University of Texas Health Science Center, San Antonio, Texas, USA since 2018. His primary research focus includes exploring DNA repair mechanisms with biochemistry and cell biology approaches. Formerly, he was a CSIR fellow and completed his Ph.D. with Dr. Shilpee Dutt from Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Navi Mumbai, India. Here, Dr. Salunkhe talks about his first author research article titled “Nuclear localization of p65 reverses therapy induced senescence” published in Journal of Cell Science (2021).

Author interview

How would you explain your paper’s key results to the non-scientific community?
Glioblastoma is one of the most difficult-to-treat types of brain tumors and is highly prone to relapse. Conventional treatment involves surgical removal followed by radiation. Despite this, some tumor cells either resist treatment or escape detection, which often leads to relapse.

Our study shows that prolonged treatment with Ciprofloxacin causes glioblastoma cells to enter a state called senescence—a kind of permanent cell cycle arrest. This happens gradually over 2 to 3 weeks. However, if treatment is stopped midway, the cells that appear senescent may resume division and become more aggressive. We call this reversible state “pseudo-senescence.”

We identified that a protein named p65 (RELA), a subunit of the NF-kappa-B complex, plays a key role in this process. Blocking p65 using a drug like JSH23 helps prevent the reversal of senescence. These findings were validated using an orthotopic glioblastoma mice model, which closely resembles human glioblastoma.

“We believe that we are still scratching the surface and there are more important events yet to be discovered, alongside key molecules which could prove therapeutically important.”

What are the possible consequences of these findings for your research area?
There are huge implications for using pro-senescence therapy to treat resistant tumors. This approach is particularly relevant in light of new tumors formed due to circulating tumor cells or chromatin fragments after harsh treatments. Halting tumor cell division is challenging, and many key molecular players are still unknown. Our study adds valuable insight into therapy-induced senescence and the role of p65 in possibly reversing it.

What was the exciting moment (eureka moment) during your research?
Two moments stand out. First, using flow cytometry, we were able to sort senescent and non-senescent cells and showed both could still form tumors in mice. Second, the discovery of nuclear translocation of p65 that dynamically controls senescence reversal was a key turning point in shaping our story mechanistically.

What do you hope to do next?
We aim to trace the presence or absence of nuclear p65 in patient biopsy samples using histopathology. This could help doctors optimize treatment timelines based on molecular events in the tumor.

Where do you seek scientific inspiration?
Rather than drawing inspiration from success stories, I find motivation in the questions themselves. If a problem evokes deep curiosity, that’s enough to spark the journey. Every small breakthrough along the way inspires the next step.

How do you intend to help Indian science improve?
Currently, I’m pursuing postdoctoral research in Texas, focusing on DNA repair biochemistry. I intend to bring the expertise I gain here back to India, establish my lab, and help Indian students—who are already highly competitive—advance their scientific careers meaningfully.

Reference
Sameer Salunkhe, Saket V. Mishra, Jyothi Nair, Sanket Shah, Nilesh Gardi, Rahul Thorat, Debashmita Sarkar, Jacinth Rajendra, Ekjot Kaur, Shilpee Dutt (2021). Nuclear localization of p65 reverses therapy induced senescence. Journal of Cell Science: jcs.253203