Tagged: Ovarian Cancer

PRDX1 Identified as Key to Chemotherapy Resistance in Cancer Cells

“[…] targeting PRDX1 should sensitize tumours to DNA-damaging agents.”

Scientists have uncovered a promising new strategy to weaken cancer cells’ natural defense mechanisms, potentially making chemotherapy more effective. In a study published in Volume 16 of Oncotarget, researchers identified the protein PRDX1 as a key player in helping tumors resist treatment. By targeting this protein, they propose a novel way to combat aggressive, treatment-resistant cancers.

Understanding Why Some Cancers Resist Treatment

Chemotherapy works by damaging the DNA of cancer cells, forcing them to self-destruct. However, many cancers develop robust repair systems that fix this damage, allowing the tumor to survive and grow. A central component of this repair machinery is a protein called ATM, which acts like a first responder in the cell, detecting DNA damage and coordinating its repair.

In ovarian cancer and other aggressive tumors, high levels of ATM have been associated with poor survival rates and resistance to chemotherapy.

The Study: How PRDX1 Protects Cancer Cells

The study, titled PRDX1 protects ATM from arsenite-induced proteotoxicity and maintains its stability during DNA damage signaling,” was led by first author Reem Ali and corresponding author Dindial Ramotar from Hamad Bin Khalifa University in Qatar, in collaboration with researchers from the University of Nottingham in the UK. 

To investigate PRDX1’s role, the team used human cell line models where they inactivated the PRDX1 gene to see how the cells would behave without it. Next, they exposed these cells to arsenite—a toxic substance that damages DNA—as well as to chemotherapy drugs and ATM inhibitors. This allowed them to observe how the absence of PRDX1 affected the cells’ ability to survive and repair damage.

They also analyzed 183 tumor samples from ovarian cancer patients, studying the levels of PRDX1, ATM, and another DNA repair protein called MRE11, and associating these findings with patient outcomes.

The Results: PRDX1 as a Key Protector 

The researchers discovered that PRDX1 physically interacts with ATM, acting as a stabilizer and protector for this critical DNA repair protein. When PRDX1 was removed from cancer cells in laboratory experiments, ATM levels decreased dramatically. Without PRDX1, the cells lost their ability to repair DNA damage and became highly sensitive to DNA-damaging agents, such as arsenite, known to harm DNA and proteins. These compromised cells were even more vulnerable when exposed to a combination of arsenite and ATM inhibitors, resulting in rapid cell death.

In tissue samples from ovarian cancer patients, tumors that had high amounts of both PRDX1 and ATM were associated with worse patient’ survival rates and were less responsive to platinum-based chemotherapy, which is a standard treatment for ovarian cancer.

Implications: A New Strategy Against Chemotherapy Resistance

This research positions PRDX1 as both a protector of cancer cells and a potential weak point. By disrupting PRDX1’s protective role, scientists believe they can sensitize resistant tumors to platinum-based chemotherapy, which is widely used for ovarian and other cancers.

The findings also raise the possibility of using PRDX1 as a biomarker to predict which tumors are more likely to respond to DNA-damaging therapies. For patients whose cancers show high PRDX1 levels, combining existing drugs with PRDX1 inhibitors, or even small doses of arsenite, might enhance treatment outcomes.

Future Perspectives and Conclusion

While these study findings are still in the experimental stage, they offer a new approach to overcoming one of cancer treatment’s greatest challenges: resistance. The next steps involve developing safe ways to block PRDX1 in patients and testing this strategy in clinical trials.

If successful, targeting PRDX1 could open the door to combination therapies that make chemotherapy more effective, reduce toxic side effects, and improve treatment options for patients with some of the hardest-to-treat cancers.

Click here to read the full research paper in Oncotarget.

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Trending With Impact: Targeted Treatment for Recurrent Ovarian Cancer

In this 2018 paper, researchers studied a new targeted strategy to treat ovarian cancer.

Anatomy and physiology of Ovary under the microscopic in laboratory.
Anatomy and physiology of Ovary under the microscopic in laboratory.

The Trending with Impact series highlights Oncotarget publications attracting higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Oncotarget.com.

Listen to an audio version of this article

Sialyl-Thomsen-nouveau (STn)—a tumor stem cell-associated carbohydrate antigen—is a moiety. “Moiety” is a term used to name molecular particles identified among multiple types of molecules. STns have been found on protein markers of cancer stem cells (CSCs) in pancreatic, colon, and gastric malignancies. Researchers hypothesize that CSCs can survive adjuvant chemotherapy and are responsible for tumor resurgence in many cancers, including recurrent ovarian cancer (OvCa). 

“Unfortunately, despite aggressive surgery and adjuvant chemotherapy, most women with OvCa develop recurrent disease that is ineffectively treated with current therapies. Novel treatment strategies are urgently needed to target chemoresistant disease.”

Researchers from Massachusetts General Hospital, Siamab Therapeutics, Inc., and Harvard Medical School conducted a novel research study in 2018 and authored a paper published by Oncotarget, entitled, “Treatment of ovarian cancer by targeting the tumor stem cell-associated carbohydrate antigen, Sialyl-Thomsen-nouveau.”

“Accumulating research has revealed not only the importance of CSCs in tumor initiation, metastasis, recurrence, and chemoresistance, but also the potential of CSC-directed therapies to impact patient survival.”

The Study

Researchers often use CD133 (a cell surface antigen) as a marker to detect and sequester CSCs in various solid tumors. In this study, the team analyzed the expression of STn and CD133 in ovarian cancer cell lines, their colony and sphere formation capacity, response to cytotoxic chemotherapy, and STn’s response to two targeted antibody drug conjugate (anti-STn-ADC) treatments in vivo and in vitro

“Analyses of colony and sphere forming capacity and of response to standard-of-care cytotoxic therapy suggest a subset of OvCa STn+ cells display some CSC features.”

In a subset of human OvCa cell lines, the researchers found that STn and CD133 were co-expressed. They also found that STn+ and CD133+ cells have increased colony formation capacity and elevated levels of STn increases sphere formation. Both of the anti-STn-ADC treatments had anti-cancer effects in the OvCa cell lines in vivo and in vitro. These findings show that STn demonstrates some stem-like properties and may be a viable therapeutic target in ovarian cancer.

“In summary, STn+ cells demonstrate some stem-like properties and specific therapeutic targeting of STn in ovarian tumors may be an effective clinical strategy to eliminate both STn+ CSC and STn+ non-CSC populations.”

Conclusion

“Our finding that targeting STn+ cells in vivo with a highly specific antibody conjugated to auristatin resulted in marked decreases in tumor burden without any obvious toxicity suggests that an anti-STn ADC approach may serve as a viable option in eliminating non-CSC as well as some CSC populations.”

Click here to read the full scientific study, published by Oncotarget.

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