Researchers at IISER Bhopal have found that depleting the production of a specific protein kinase (PAK2) has a cascading effect in head and neck cancer. The expression of both cancer gene (c-Myc) and cancer-specific metabolic enzyme (PKM2) gets compromised when PAK2 protein is depleted. Inhibitors developed to target the PAK2 protein are more likely to be successful in treating head and neck cancer and reducing resistance to cancer drugs.
Researchers at the Indian Institute of Science Education and Research (IISER) Bhopal have found that depleting the production of a specific protein kinase (p21-activated kinase 2 or PAK2), which is normally produced in excess in head and neck cancer, affects a chain of events that finally reduces the growth of head and neck cancer.
In cancer cells, the PAK2 protein is responsible for increased cell proliferation, cell migration, invasion into the extracellular matrix, colony formation and even resistance to certain cancer drugs. The team led by Prof. Sanjeev Shukla from the Institute’s Department of Biological Sciences found the PAK2 protein was produced in excess (overexpressed) in 24 of 26 human cancer samples.
When the production of this protein was reduced in three head and neck cancer cell lines, the cancer cells became less viable and had reduced ability to proliferate, migrate, form colony and even resist cancer drugs. These studies showed the importance of interfering with PAK2 protein levels to control head and neck cancer. So the researchers set to find the molecular mechanism behind the role of PAK2 protein in cancer growth.
“What we found was when the PAK2 protein level was reduced, the activation of a certain (beta-catenin) signalling pathway was inhibited,” says Prof. Shukla, who is a Wellcome Trust/DBT India Alliance Fellow. This pathway is important as its activation is associated with downstream target genes that play an important role in cancer growth. “So we hypothesised that the beta-catenin signalling might be dependent on PAK2 protein level and inhibiting the pathway will affect the expression of a well known cancer gene c-Myc,” he says. The c-Myc gene is produced in excess in head and neck cancer and is responsible for cancer cell growth.
“When we depleted the amount of PAK2 protein in cancer cells we found the activity of the signalling pathway getting affected, which then led to reduced expression of the cancer gene,” says Amit Gupta the Institute’s Department of Biological Sciences and first author of a paper in the journal Cell Death & Disease.
In a cascade of events, the reduced expression of the cancer gene causes a reduction in the amount of a cancer-specific metabolic enzyme (pyruvate kinase M2 or PKM2) produced. The PKM2 enzyme plays an important role in increasing the rate at which the glucose gets converted into lactate in cancer cells, which provides energy and also supports rapid cell division by providing the building blocks for forming new cells. So any reduction in this enzyme level severely compromises cancer cells’ ability to proliferate and migrate.
Unlike in normal cells, the glucose metabolism is not complete in cancer cells. So the glucose gets converted into lactate leading to less energy availability in cancer cells. Cancer cells tend to compensate for this by increasing the rate of glucose to lactate conversion and also by taking up more glucose from the surrounding environment.
“The involvement of PAK2 protein in other cancers is already known. But the cascading effect of PAK2 depletion in compromising the expression of the cancer gene (c-Myc) and cancer-specific metabolic enzyme (PKM2) was not known,” says Prof. Shukla. “This is the first study to report this and its role in head and neck cancer progression.”
“It might be possible to develop inhibitors to target the PAK2 protein to help treat head and neck cancer. More studies are needed before inhibitors are used but there is a potential,” says Prof. Shukla.
“The PAK2 protein is also responsible for chemotherapeutic resistance. So it might be possible to enhance the efficacy of currently available cancer drugs by combining them with PAK2 inhibitors,” says Gupta.