Stopping HK2 in Breast Cancer Tumors Could Be Potential Cure For Metastasis

University of Illinois Cancer Center member Nissim Hay, PhD, has conducted years of groundbreaking research on breast cancer, with his work being published in numerous high-impact journals. The latest work from his laboratory, titled “A non-catalytic scaffolding activity of hexokinase 2 contributes to EMT and metastasis” has been published in Nature Communications. Catherine “Casey” Blaha, a MD/PhD student mentored by Hay, professor of biochemistry and molecular genetics at the University of Illinois College of Medicine, is first author on the paper, which is a first for her. We asked Blaha to describe the new research.

“A non-catalytic scaffolding activity of hexokinase 2 contributes to EMT and metastasis”

Your latest work has found that eliminating a critical metabolic enzyme – hexokinase 2, or HK2 – in a mouse model of metastatic breast cancer greatly reduces the amount of metastasis to the lungs in those mice. How did you arrive at this conclusion?

Blaha: We sought to investigate the role of HK2 in breast cancer metastasis given its high morbidity and mortality. The requirement of HK2 for cancer development was attributed to its glycolytic activity to fulfill the metabolic demands of cancer cells. In our paper, we show that HK2 possesses a moonlighting non-glycolytic activity that contributes to metastasis.

We discovered that deleting HK2 after the primary tumor has formed inhibited lung metastasis without any adverse consequences. Surprisingly, however, the role of HK2 in breast cancer metastasis not only depends on its glycolytic activity, but it also has a non-catalytic function, contributing to the spread of the cancer. We demonstrated that HK2 functions as an A-kinase anchoring protein, acting as a scaffold to aid in the inhibitory phosphorylation of glycogen synthase kinase 3 beta (GSK3B). GSK3B can phosphorylate proteins and target them for degradation.

Is there a specific GSK3B target that you studied?

Blaha: One of the proteins targeted is called SNAIL, which is known to promote metastasis. Therefore, high HK2 levels in breast cancer facilitates breast cancer metastasis, at least in part, by increasing SNAIL protein levels.

Breast cancer is the most common cancer diagnosed among U.S. women and is the second leading cause of death among women after lung cancer. It accounts for about 30% (or one in three) of all new female cancers each year. How will patients benefit from your latest research?

Blaha: This research helps to uncover different ways breast cancer can spread throughout the body. As a result, we provide evidence that inhibition of HK2 after tumor onset could be a

potential therapeutic intervention for breast cancer metastasis.

The research was supported by NIH grants R01AG016927, R01CA090764, and R01 CA206167, F30CA228191, Veteran’s Administration merit award BX000733, and the VA research career scientist award IK6BX004602.

Translate »