Sunday, March 26, 2023

Switching off gene makes cancer cells more sensitive to chemotherapy

Good news! Cancer is history (soon)! 

Looks like cancer is a lot more clever than heretofore known. Activating DNA cell repair to resist or counteract chemotherapy is a good one!

"... A process called epithelial-mesenchymal transition (EMT) has been shown to control cancer tumor development, progression, and metastasis, as well as resistance to chemotherapy. Through EMT, epithelial cancer cells lose their ability to adhere to neighboring cells, gaining increased migratory and invasive capabilities. But the mechanism by which EMT affects chemotherapy resistance is not well understood. Researchers ... experimented on mice genetically modified to have skin squamous cell carcinoma (SCC), the second most common type of skin cancer. The researchers examined cancer cells presenting EMT to investigate the response different cell populations had to chemotherapy. ...
The researchers found that the EMT-presenting cancer cells were very resistant to chemotherapy and that in the chemotherapy-resistant cells, expression of the RHOJ gene was high. The gene encodes a small GTP-binding protein that is also called RHOJ. GTP-binding proteins transmit signals outside the cell, causing intracellular changes.
Importantly, the researchers found that silencing RHOJ expression made the cancer cells sensitive to chemotherapy. Taking a closer look at the RHOJ protein, they discovered the mechanism by which RHOJ makes cells chemotherapy resistant. RHOJ was found to activate the DNA repair pathway in a cell after DNA damage was caused by chemotherapy. This allowed cancer cells to repair themselves and escape death. ..."

From the abstract:
"The resistance of cancer cells to therapy is responsible for the death of most patients with cancer. Epithelial-to-mesenchymal transition (EMT) has been associated with resistance to therapy in different cancer cells. However, the mechanisms by which EMT mediates resistance to therapy remain poorly understood. Here, using a mouse model of skin squamous cell carcinoma undergoing spontaneous EMT during tumorigenesis, we found that EMT tumour cells are highly resistant to a wide range of anti-cancer therapies both in vivo and in vitro. Using gain and loss of function studies in vitro and in vivo, we found that RHOJ—a small GTPase that is preferentially expressed in EMT cancer cells—controls resistance to therapy. Using genome-wide transcriptomic and proteomic profiling, we found that RHOJ regulates EMT-associated resistance to chemotherapy by enhancing the response to replicative stress and activating the DNA-damage response, enabling tumour cells to rapidly repair DNA lesions induced by chemotherapy. RHOJ interacts with proteins that regulate nuclear actin, and inhibition of actin polymerization sensitizes EMT tumour cells to chemotherapy-induced cell death in a RHOJ-dependent manner. Together, our study uncovers the role and the mechanisms through which RHOJ acts as a key regulator of EMT-associated resistance to chemotherapy."

Switching off gene makes cancer cells more sensitive to chemotherapy


Extended Data Fig. 6: RHOJ promotes DNA repair in EMT tumour cells independently of ATM and ATR


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