Johns Hopkins Discovers a Protein That Contributes to Ovarian Cancer Recurrence By Causing Chemoresistance

” … Ground-breaking work on an ovarian cancer-related protein in the lab of Ie-Ming Shih at the [Johns Hopkins] School of Medicine is leading to new insights into cancer biology. … They have revealed a novel protein that creates cancer cells that are resistant to traditional cancer chemotherapies and partially revealed its mechanism of action. With all of this information, the team hopes to create drugs that can target these proteins or find out which chemotherapies currently on the market do not function in this pathway to create resistant cancer cells.”

“Ovarian cancer is a growing concern with more than 15,000 deaths occurring in 2007, making it the leading cause of death in gynecological diseases.

Ie-Ming Shih, M.D., Ph.D., Professor, Pathobiology Graduate Program, Department of Pathology, Johns Hopkins University, Baltimore, Maryland

Ie-Ming Shih, M.D., Ph.D., Professor, Pathobiology Graduate Program, Department of Pathology, Johns Hopkins University, Baltimore, Maryland

Ground-breaking work on an ovarian cancer-related protein in the lab of Ie-Ming Shih at the School of Medicine is leading to new insights into cancer biology.

The protein is nucleus accumbens-1, NAC-1, which is a transcription factor that regulates the expression of genes. Previous work has shown NAC-1 to be overexpressed in many types of cancer, specifically ovarian cancer that is resistant to chemotherapy.

A deeper understanding of its mechanism of action would allow scientists and physicians to make inroads into possibly curing the diseases.

In many cases, the first round of chemotherapy or treatment shrinks the tumor but does not cure the patient of the diseases. The cancer then grows back and can be resistant to a second round of the initial therapy.

Ovarian cancer cells that are resistant to chemotherapy have higher than normal levels of NAC-1. Shih and her [sic] team showed that the ovarian cancer cells, when exposed to a particular chemotherapy drug, were resistant compared to cancer cells with normal expression of NAC-1.

Upon further investigation into the biological pathways of interacting proteins in the nucleus, the team found that another protein [Gadd45-gamma-interacting protein 1 (Gadd45gip1)] is the target of NAC-1’s mechanism of action.

NAC-1 works by interacting with this other protein and stopping it from working and decreasing its expression inside the cell. So when NAC-1 expression is increased, the cancer cells are resistant to treatment, and the downstream target protein of NAC-1 is downregulated.

Performing further experiments, the researchers found that by making normal cancer cells overexpress the NAC-1 protein the cells were resistant to the chemotherapy drug, where previously they were not before the induced expression.

Also, the downstream target protein had reduced expression.

Conversely, if the researchers knocked down the expression of NAC-1 or increased the expression of its downstream target protein, then the cells were sensitive to cancer treatment, more so than normal cancer cells.

The scientists also wanted to uncover how the proteins interact structurally. Their work has revealed that NAC-1 is a homodimer protein, meaning it self-dimerizes – two copies of the protein come together to form the working product.

If the researchers formed a NAC-1 protein with only one of the units working properly, then the entire protein would not function and the ovarian cancer cells were sensitive to chemotherapy treatment.

Also, in this non-functional protein, it would induce the expression of its downstream target protein and increase that protein’s expression, thereby sensitizing the cells to chemotherapy.

Taken together, the researchers have paved new roads into the ever-complicating fight against cancer.

They have revealed a novel protein that creates cancer cells that are resistant to traditional cancer chemotherapies and partially revealed its mechanism of action.

With all of this information, the team hopes to create drugs that can target these proteins or find out which chemotherapies currently on the market do not function in this pathway to create resistant cancer cells.”

Source: Resistance to cancer chemotherapy is studied, by Neil Neumann, Science Section, The Johns Hopkins Newsletter, April 2, 2009 (discussing Jinawath N, Vasoontara C, Yap KL et al.  NAC-1, a potential stem cell pluripotency factor, contributes to paclitaxel resistance in ovarian cancer through inactivating Gadd45 pathwayOncogene. 2009 Mar 23. [Epub ahead of print]).

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