Researchers Reveal a Key Mechanism: How Cancer Cells Promote Their Chemoresistance


Source: Howard University

Summary: Researchers reported that RECQ1, a breast cancer susceptibility gene potentially acts as a defense against chemotherapeutics and helps in promoting chemoresistance in cancer cells.


Genomic instability is one of the key hallmarks of cancer development. Human DNA is constantly challenged by endogenous and exogenous sources that induce DNA damage. The cells are equipped with DNA repair mechanisms that combat the damage and play an important role in the maintenance of genomic stability. Germline mutations in DNA repair genes lead to disorders that are often associated with increased genome instability. A kind of resistance is acquired by certain cancer cells to act against chemotherapy drugs, called as chemoresistance. Cancer drug resistance exists to be a major challenge in the field of oncology and tumor cells develop resistance prior to or as a result of cancer therapy.

One of the mechanisms by which cancer cells gain chemoresistance is to upregulate the expression of certain DNA repair genes to combat the DNA damage induced by chemotherapeutic agents. The upregulation of these genes in highly proliferative cancer cells is believed to be a general adaptive response to chronic replication stress (a phenomenon that occurs during DNA replication and can result in stalled replication fork). Researchers from the Howard University and National Cancer Institute reported one such breast cancer susceptibility gene, RECQ1, a DNA repair helicase potentially acts as a defense against chemotherapeutics and helps in promoting the chemoresistance ability of cancer cells. The research findings were published in the journal Oncotarget.

Cancer cells develop resistance against chemotherapy drugs

Credit: NIH

To figure out if RECQ1 is involved in repair of DNA damage induced by different chemotherapeutic drugs, the research team led by Dr. Sudha Sharma, treated different cancer cells with chemotherapeutic drugs such as MMS (Methylmethanesulfonate), Temozolamide, Fotemustine, Gemcitabine and demonstrated that RECQ1 is upregulated at mRNA and protein level in response to DNA damage induced by different drugs. This study shows that RECQ1 is a direct target of p53 and its expression upon DNA damage is regulated by p53. Depletion of RECQ1 sensitizes cancer cells to the chemotherapeutics tested indicating that these cells rely on RECQ1 functions to survive. These results identify a previously unrecognized p53-mediated upregulation of RECQ1 expression in response to DNA damage and implicate RECQ1 in the repair of DNA lesions including those induced by alkylating and other chemotherapeutic agents.

Principal Investigator of the study, Dr. Sudha Sharma said, “RECQ1 expression correlates to patient’s survival in breast cancers and therefore, RECQ1 can be used as a biomarker and indicate potential development of helicase inhibitors as anti-cancer agents for improved therapeutic outcome.”


More Information: Swetha Parvathaneni et al, “RECQ1 expression is upregulated in response to DNA damage and in a p53-dependent manner”, Oncotarget (2017). DOI: http://dx.doi.org/10.18632/oncotarget.18237


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