DnaK: A Bacterial Protein Involved In Anticancer Drug-resistance

DnaK, a protein of the bacterium mycoplasma, interferes with the mycoplasma-infected cell’s ability to respond to and repair DNA damage, a known origin of cancer, the Institute of Human Virology (IHV) at the University of Maryland School of Medicine (UMSOM) repoprts.

Little or no mycoplasma DnaK DNA sequences were found associated with the tumor, which was fully developed, suggesting a hit-and-run or hide mechanism of transformation, indicating that the damage is done early, but the protein may not be needed once the cancer cells are formed.

“Currently, approximately 20% of cancers are thought to be caused by infection, most are known to be due to viruses. Mycoplasmas are a family of bacteria that are associated with cancers, especially in people with HIV. Our work provides an explanation for how a bacterial infection can trigger a series of events that lead to cancer. Of particular importance, the infection did not need to persist and the protein did not need to be continuously present in all cancer cells. The study also provides a mechanism for how some bacterial infections can interfere with specific cancer drugs,”

said Robert Gallo, MD.

Mycoplasma Infection

Researchers utilized immune-compromised mice as a model for analyzing the effect of mycoplasma infection on the development of lymphoma. They compared how quickly non-infected immune-compromised mice developed lymphoma compared to mycoplasma-infected immune-compromised mice.

The mice were infected with a strain of mycoplasma from an HIV patient. The researchers found that mycoplasma infection caused the mice to develop lymphoma earlier in life than non-infected immune-compromised mice and that some, but not all, of the cancer cells had bacterial DNA.

Finding only a small amount of bacterial DNA in the cancer cells suggested that the infection did not have to persist to trigger cancer.

The study was conducted by Robert Gallo, MD, The Homer & Martha Gudelsky Distinguished Professor in Medicine and Co-Founder and Director, Institute of Human Virology, University of Maryland School of Medicine and Davide Zella, Ph.D., Assistant Professor of Biochemistry and Molecular Biology, Institute of Human Virology, University of Maryland School of Medicine. Drs. Gallo and Zella collaborated with Hervé Tettelin, Ph.D., Associate Professor of Microbiology and Immunology, Institute for Genome Sciences, University of Maryland School of Medicine.

“We focused on a protein called DnaK, which is part of a family of proteins that function as a ‘chaperone’ for other proteins protecting them from damage or helping them to fold. However, in this case, DnaK reduces the activity of important cellular proteins involved in DNA repair and anti-cancer-activities, such as p53. Thus, cells infected with mycoplasma would not be able to properly repair damaged DNA, thus, potentially increasing the risk for cancer development,”

said Dr. Zella.

Different DnaK Sequences

The scientists noted that the bacteria can release DnaK and the DnaK enters nearby uninfected cells. The study also demonstrates that by reducing p53, DnaK can also reduce the efficacy of anti-cancer drugs.

Thus, mycoplasma infection could not only trigger events leading to the accumulation of DNA damage and oncogenesis in infected cells, but also trigger cancer-causing events in nearby uninfected cells that took up DnaK released from infected neighboring cells.

“We analyzed the amino acid sequences of DnaK from many bacteria and found that the DnaK proteins from bacteria associated with cancer grouped together were different DnaK sequences from bacteria that are not associated with cancer. This raises the possibility that other bacteria have the same cancer-promoting ability,”

said Dr. Tettelin.

“This hit-and-run, or hide, mechanism mediated by a protein common to many cancer-associated bacteria changes how we need to think about infection and at least some cancers. Furthermore, this provides a basis for understanding how infection can influence the effectiveness of some cancer treatments,”

Dr. Gallo said.

Davide Zella, Sabrina Curreli, Francesca Benedetti, Selvi Krishnan, Fiorenza Cocchi, Olga S. Latinovic, Frank Denaro, Fabio Romerio, Muhammad Djavani, Man E. Charurat, Joseph L. Bryant, Hervé Tettelin, Robert C. Gallo
Mycoplasma promotes malignant transformation in vivo, and its DnaK, a bacterial chaperon protein, has broad oncogenic properties
Proceedings of the National Academy of Sciences Dec 2018, 201815660; DOI: 10.1073/pnas.1815660115

Image: Michele Studer, Wellcome Images