Mechanisms of therapy induced senescence reversal

Dr. Sameer Salunkhe’s interview with Bio Patrika hosting “Vigyan Patrika”, a series of author interviews. 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).

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How would you explain your paper’s key results to the non-scientific community?

Glioblastoma is one of the most difficult to treat type of brain tumors and has a high propensity for the reappearance, also called relapse. The conventional treatment involves surgical removal of the tumor and radiation treatment, to burn down any remaining tumor traces. Despite this dual treatment some of the tumor cells are either resistant to the treatment or escape due to the inability to detect or operate the tumor area. So the key difficulty in the treatment is those residual cells that need to be taken care of, else relapse is almost inevitable.


Figure 1. Represents simplified results from JCS research article (doi: 10.1242/jcs.253203).

According to our work, prolonged treatment of Ciprofloxacin affects the cell division capacity of glioblastoma cells and eventually puts them under permanent cell division arrest i.e. senescence state. This is a gradual process and takes between 2 to 3 weeks to achieve. We observe that interrupting Ciprofloxacin treatment in the middle of the process even though the cell appears to attain senescence (by typical senescence detection assays- such as Beta-galactosidase activity, DNA damage or cellular morphology) leads to a resumption of cell division and often turn aggressive. We refer this in-between time frame window, where cells seem to be senescent but are not as “pseudo-senescent stage.” Next, we identify a key protein (i.e., p65 (RELA), a subunit of the NF-kappa-B complex) responsible for this reversible process. Blocking the functions of p65 using drugs such as JSH23 (a chemical inhibitor) prevents glioblastoma cells from dodging senescence and can act as a safeguard during the treatment. These findings also were confirmed using the orthotopic glioblastoma mice model (a highly comparable animal model system to study 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 immense implications of using pro-senescence therapy in cancer treatment and it could be relevant to most kinds of therapy-resistant tumors. This method of combating cancer is even more so important in light of the formation of secondary tumors due to either circulating tumor cells or chromatin fragments, which are the byproducts of more aggressive chemo or radiation therapy. Halting tumor cell division is challenging, and many players of this process are still to be discovered. Studies like ours help understand the mechanisms of therapy-induced senescence, and yield molecules such as p65, which are therapeutically relevant and provide possible explanation on how senescence could be reversible. 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 was the exciting moment (eureka moment) during your research?

Every little step is critically important when we try something as challenging as understanding senescence induction and reversal, especially when experiments are to be done with living cells and animal models for an extended time duration. However, for me there were two key eureka moments, I came across during the project. The first one was when we were able to sort the senescent and non-senescent cells using flow cytometry and showed that both cells could form tumors in the mice. The second, perhaps the one that shaped the story mechanistically was the nuclear translocation of p65, which dynamically regulated the process of senescence reversal.

What do you hope to do next?

With the hope that the absence or presence of p65 during the treatment regime can also be traced into patient samples biopsies (Using histopathological examination of nuclear p65). We would like to take our findings ahead and hope to help clinicians decide the timeline for treatment based on molecular events.

Where do you seek scientific inspiration?

Personally, I don’t seek inspiration in the memoir of successful individuals. Well, the inspiration for me comes from two aspects. The foremost is if the problem that we want to address brings enough inquisitiveness along? And once I begin with the project, every small breakthrough attained through the process inspires me to make the next move.

How do you intend to help Indian science improve?

I am pursuing my postdoctoral studies at the University of Health Science Center at San Antonio (UTHSCSA) Texas, USA, and my major focus is on DNA repair biochemistry. I would certainly want to bring expertise that I would gain during my tenure as a postdoctoral researcher back home, run my laboratory, and help Indian students (Who are already very competitive) to shape their scientific journey in the best possible manner.

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

Email: sameer25787@gmail.com

Dr. Shilpee Dutt lab: https://www.shilpeeduttlab.com/

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