Culprit Behind Increase of Radioresistant Cancer Cells Revealed

Culprit Behind Increase of Radioresistant Cancer Cells Revealed

Radiation is one of the most common treatments for cancer. Radiation therapy uses high-energy particles or waves, such as x-rays, gamma rays, electron beams, or protons, to destroy or damage cancer cells. It makes small breaks in the DNA inside cells to keep cancer cells from growing and dividing and cause them to die. Nearby normal cells can also be affected by radiation, but most recover and go back to working the way they should. Unfortunately, there are varieties of cancer that become resistant to these therapies, and in some cases, these radioresistant cancers can become more invasive following treatment, worsening the prognosis for the patient.

Now, scientists from the Global Center for Biomedical Science and Engineering, a collaboration between Hokkaido University in Japan, and Stanford University, have discovered the mechanism by which molecules called Arl8b and BORC cause increased invasiveness and metastasis in radioresistant cancer cells following radiotherapy.

Their findings were published in the journal Communications Biology in a paper titled, “Lysosomal trafficking mediated by Arl8b and BORC promotes invasion of cancer cells that survive radiation.”

The Molecular and Cellular Dynamics Research Group at Hokkaido University. Yasuhito Onodera (bottom row, left), Ping-Hsiu Wu (bottom row, center right), and Jin-Min Nam (bottom row, right) contributed to this paper 
[Global Center for Biomedical Science and Engineering.]

“Enhanced invasiveness, a critical determinant of metastasis and poor prognosis, has been observed in cancer cells that survive cancer therapy, including radiotherapy,” noted the researchers. “Here, we show that invasiveness in radiation-surviving cancer cells is associated with alterations in lysosomal exocytosis caused by the enhanced activation of Arl8b, a small GTPase that regulates lysosomal trafficking. The binding of Arl8b with its effector, SKIP, is increased after radiation through the regulation of BORC-subunits. Knockdown of Arl8b or BORC-subunits decreases lysosomal exocytosis and the invasiveness of radiation-surviving cells.”

Previous work and studies have shown that vesicle trafficking, including endocytosis, recycling, and the exocytosis of proteins and organelles, plays an essential role in cancer invasion. Recent studies have highlighted the important roles lysosomes play in tumor biology. The researchers confirmed that the trafficking of lysosomes was upregulated in the cancer cells following radiotherapy, enhancing the secretion of enzymes that degrade the connective material surrounding them, and therefore increasing the invasiveness of the cancer cells. They further investigated the molecular mechanisms behind this activity and determined that a regulatory molecule, Arl8b, is primarily responsible for this process.

Fluorescence micrograph of breast cancer cell line showing the lysosome (green), DNA (blue), and cell skeleton (red). [Ping-Hsiu Wu]

The researchers analyzed data on breast cancer patients from the Cancer Genome Atlas (TCGA) to identify other molecules that may be involved.  In addition to Arl8b levels, prognosis can be correlated with levels of a group of proteins called BORC complex. BORC was found to be required for the association of Arl8b and lysosomes, suggesting that certain BORC subunits are required for the increased invasiveness of radioresistant cancer cells mediated by Arl8b.

The findings suggest that lysosomes can be targeted for therapy of highly metastatic cancer, and may lead to the development of new strategies to combat radioresistant cancer cells and improve cancer treatment.