A Way to Kill Chemo-Resistant Ovarian Cancer Cells: Cut Down Their Protector

A recent study provides new insight into why ovarian cancer is often resistant to chemotherapy, as well as a potential way to improve its diagnosis and treatment.

Protein Data Base 3-D rendering of the gelsolin protein. (Photo: Wikipedia)

Ovarian cancer is the most lethal gynecological cancer, claiming the lives of more than 60% of women who are diagnosed with the disease. A study involving Ottawa and Taiwan researchers, published in the influential Proceedings of the National Academy of Sciences (PNAS), provides new insight into why ovarian cancer is often resistant to chemotherapy, as well as a potential way to improve its diagnosis and treatment.

It is estimated that 2,700 Canadian women will be diagnosed with ovarian cancer in 2014 and that 1,750 Canadian women will die from the disease, according to Ovarian Cancer Canada. This cancer is often diagnosed late and develops a resistance to chemotherapy.

Dr. Ben Tsang

“What we’ve discovered will help clinicians to better treat women with ovarian cancer,” says Dr. Ben Tsang, senior scientist at the Ottawa Hospital Research Institute and professor at the University of Ottawa. “The key is understanding the role of a protein called “gelsolin.” With our colleagues from National Cheng Kung University in Taiwan, we found that an increased level of this protein is associated with aggressive forms of ovarian cancer that are more likely to be resistant to chemotherapy and lead to death.”

The researchers showed how gelsolin works at the molecular level to protect cancer cells against a widely used chemotherapy drug called “cisplatin.”

The findings are important because they will help clinicians to determine the most effective treatment plan based on the level of gelsolin. Work still needs to be done to determine exactly how much gelsolin indicates a cancer that is chemo-resistant and would require different treatment options.

In addition, this same protein that makes ovarian cancer cells resistant to chemotherapy can be used to overcome this treatment obstacle. By cutting gelsolin down to a specific fragment and putting it into chemo-resistant cancer cells, the international team discovered they could make these cells susceptible to the cancer-killing effects of cisplatin.

Dr. Dar-Bin Shieh

“We believe this discovery is a promising avenue for developing a new therapy to reduce chemo-resistance in women with this deadly disease,” said Dr. Dar-Bin Shieh, collaborative partner from National Cheng Kung University of Taiwan. Shieh is currently leading the International Institute of Macromolecular Analysis and Nanomedicine Innovation (IMANI), which is focused on translating molecular discoveries to the clinic.

Based on 2009 estimates, approximately one in 72 Canadian women will develop ovarian cancer in her lifetime and one in 93 will die from it.

This study was supported by the Canadian Institutes of Health Research and the National Science Council of Taiwan.

Ottawa Hospital Research Institute
The Ottawa Hospital Research Institute is the research arm of The Ottawa Hospital and is an affiliated institute of the University of Ottawa, closely associated with its faculties of Medicine and Health Sciences. The Ottawa Hospital Research Institute includes more than 1,700 scientists, clinical investigators, graduate students, postdoctoral fellows and staff conducting research to improve the understanding, prevention, diagnosis and treatment of human disease. Research at Ottawa Hospital Research Institute is supported by The Ottawa Hospital Foundation.

University of Ottawa: A crossroads of cultures and ideas
The University of Ottawa is home to almost 50,000 students, faculty and staff, who live, work and study in both French and English. The campus is a crossroads of cultures and disciplines, where bold minds come together to inspire game-changing ideas. The University of Ottawa is one of Canada’s top 10 research universities — our professors and researchers explore new approaches to today’s challenges. One of a handful of Canadian universities ranked among the top 200 in the world, we attract exceptional thinkers and welcome diverse perspectives from across the globe.

National Cheng Kung University
National Cheng Kung University (NCKU) is a research-led comprehensive university in Tainan City, Taiwan. Since its establishment in 1931, NCKU has nurtured countless social elites and leaders under the trailblazing efforts of its former faculties and staffs. NCKU is one of the most prestigious universities in Taiwan, with a high reputation in science, engineering, medicine, management, planning and design. The university is a role model for the transformation of Taiwan’s higher-educational institutes, and is also an important pillar of the country’s economic and industrial structure.

Sources:

• Abedini MR et al. Cell fate regulation by gelsolin in human gynecologic cancers. PNAS 2014 ; published ahead of print September 22, 2014, doi:10.1073/pnas.1401166111.
• A way to kill chemo-resistant ovarian cancer cells: Cut down its protector. Ottawa Hospital Research Institute Press Release, September 24, 2014.

“Shielded” Ovarian Cancer Cells May Survive Chemotherapy

Cancer Research UK scientists have discovered certain ovarian tumor cells that are resistant to chemotherapy can survive a first round of treatment and go on to “re-grow” the cancer.

Cancer Research UK scientists have discovered certain ovarian tumor cells that are resistant to chemotherapy can survive a first round of treatment and go on to “re-grow” the cancer. This could help explain why the disease can be difficult to treat, according to new research published in Oncogene on June 28.

The study, funded by Cancer Research UK, aimed to find out whether it is the chemotherapy itself that causes anti-cancer drug resistance to build in the body – similar to resistance to antibiotics – or if cells that are shielded against cancer treatment grow as part of the initial tumor and are already lying dormant before chemotherapy begins.

Often ovarian cancer can be hard to treat with treatment failing after women initially responded well. The number of women surviving beyond five years is less than 35 per cent.

The researchers compared the characteristics of cell lines from the tumor at the time of diagnosis to cell lines from the same patients once the disease had been treated and become resistant.

Dr. James Brenton, Researcher, Functional Genomics of Ovarian Cancer, Cambridge Research Institute

Dr. James Brenton, study author from the Cancer Research UK’s Cambridge Research Institute, said:

“Ovarian cancer is notoriously hard to treat. Women usually respond well to their first round of chemotherapy with the disease apparently completely removed.  But unfortunately many go on to relapse within six to 24 months. Until now we haven’t known whether they are becoming resistant to the treatment or whether the cells that don’t respond to treatment re-grow the tumour.

By examining the characteristics of ovarian tumours we now think that cells resistant to chemotherapy grow as part of the tumor. This means that when patients have treatment, cells that respond to chemotherapy are destroyed but this leaves behind resistant cells which then form another tumor of completely resistant cells. This seems to explain why successful treatment for relapsed patients is difficult. What needs to be developed now is a therapy designed to target the resistant cells.”

Dr. Lesley Walker, director of science information at Cancer Research UK, said:

“Discoveries like this help to tell us why chemotherapy stops working for some ovarian cancer patients. We hope it will lead to new ways to tackle the disease and increase the number of women that survive this cancer that can be so hard to cure. The next step will be to develop treatment tailored to fight the resistant cells.”

Sources:

• “Shielded” ovarian cancer cells may survive chemotherapy, Press Release, Cancer Research U.K., June 28, 2010.

• SL Cooke, CKY Ng, N Melnyk, et. al.  Genomic analysis of genetic heterogeneity and evolution in high-grade serous ovarian carcinoma. Oncogene , 28 June 2010, doi:10.1038/onc.2010.245 (epublished ahead of print).

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

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 pathway.  Oncogene. 2009 Mar 23. [Epub ahead of print]).