Dagar dissects a prostate cancer driver
Many cancer treatments block hormones that drive tumor cell division and metastasis. These therapies only shrink tumors temporarily, however, as cancer cells can use alternative signaling pathways to reduce their hormone dependence. Drugs that target these pathways may halt tumor growth and extend patient survival.
The 2020 JBC Herbert Tabor Early Career Investigator Award winners will present their work at the 2021 ASBMB Annual Meeting, 1:45–3 p.m., Tuesday, April 27.
Find out about registering for the annual meeting here.
Manisha Dagar has uncovered the details of a signaling pathway that drives advanced prostate cancer.
Dagar has always been interested in science, especially biology. Her mother encouraged her to pursue higher education and a research career. She earned an undergraduate degree in biotechnology, and a summer internship at the National Centre for Disease Control in New Delhi gave her the lab experience she needed to pursue a Ph.D. at Amity Institute of Biotechnology, Amity University in Haryana, India.
At Amity University, Dagar decided to study the molecular biology of cancer. She joined Gargi Bagchi’s lab, where she studies androgens, the male sex hormones, in prostate cancer. Previous research revealed that protein kinase A, which phosphorylates proteins to change their functions, can activate androgen signaling in the absence of hormones. Dagar and colleagues in the lab discovered how this aberrant activity contributes to prostate cancer progression.
Dagar studied protein kinase A function in a cell line derived from a prostate cancer patient. After optimizing protocols to measure protein levels in these cells, Dagar could track how blocking protein kinase A phosphorylation activity changed androgen signaling. Her work has revealed new drug targets that could treat advanced prostate cancer.
Dagar successfully defended her Ph.D. thesis in January. She hopes to pursue postdoctoral research studying cell signaling. Outside the lab, she enjoys reading and traveling.
Targeting molecular chaperones to stop prostate cancer
Testosterone and related androgen hormones act through the androgen receptor, which is stabilized in the cytoplasm by the molecular chaperone HSP90. When the receptor binds an androgen, it releases HSP90 and enters the nucleus to regulate gene expression. Androgens thus direct the development and maintenance of the prostate gland but also drive prostate cancer.
Manisha Dagar and her colleagues knocked down protein kinase A to learn how this enzyme affects androgen receptor nuclear entry. They discovered that protein kinase A phosphorylates HSP90, causing it to release the androgen receptor. The receptor then binds HSP27, a different molecular chaperone, which helps it enter the nucleus. Once in the nucleus, the receptor can bind certain DNA regions to turn on genes.
Blocking protein kinase A activity blocked testosterone-induced HSP90 phosphorylation, androgen receptor-HSP90 dissociation, androgen receptor-HSP27 binding, androgen receptor nuclear entry, changes in gene expression and increase in proliferation of prostate cancer cells.
“By targeting HSP90 phosphorylation by protein kinase A, androgen signaling in prostate cancer cells can be blocked,” Dagar said. “This can be used as a therapeutic target for treatment of prostate cancer.”
As first author on the paper reporting this research, Dagar received a 2020 Journal of Biological Chemistry/Herbert Tabor Early Career Investigator Award.
Dagar and her colleagues continue to search for ways to block prostate cancer cell proliferation, including in patients that express hormone-independent variants of the androgen receptor.
Enjoy reading ASBMB Today?
Become a member to receive the print edition monthly and the digital edition weekly.
Learn moreGet the latest from ASBMB Today
Enter your email address, and we’ll send you a weekly email with recent articles, interviews and more.
Latest in People
People highlights or most popular articles
Listen, learn and support
Four LGBTQIA+ scientists share their stories and reflect on progress and setbacks for inclusivity and support.
2023 PROLAB winners named
Ten early-career scientists will receive grants that will allow them to advance their research by working in the labs of collaborators abroad.
State laws change the landscape for LGBTQIA+ scientists
New legislation in the past 16 months has banned gender affirming care for transgender teens, teaching children about sexual orientation and gender identity, and drag shows.
Redefining STEM
The U.K.-based organization Pride in STEM says it aims to “queer up science spaces” and to “science up queer spaces.”
Awards for Medlock, Bagde and Maquat
Awards, promotions milestones and more. Find out what's going on in the lives of ASBMB members.
In memoriam: Sorina Popescu
She was a a plant biologist and biochemist whose last studies included several melding science and agriculture on topics ranging from crop stress resistance to plant root microbial community control.