Simultaneously Targeting Tissue Transglutaminase and Kidney Type Glutaminase Sensitizes Cancer Cells to Acid Toxicity and Offers New Opportunities for Therapeutic Intervention

Abstract

Most cancer cells undergo characteristic metabolic changes that are commonly referred to as the Warburg effect, with one of the hallmarks being a dramatic increase in the rate of lactic acid fermentation. This leads to the production of protons, which in turn acidifies the microenvironment surrounding tumors. Cancer cells have acquired resistance to acid toxicity, allowing them to survive and grow under these detrimental conditions. Kidney type glutaminase (GLS1), which is responsible for the conversion of glutamine to glutamate, produces ammonia as part of its catalytic activities and has been shown to modulate cellular acidity. In this study, we show that tissue, or type 2, transglutaminase (TG2), a γ-glutamyl transferase that is highly expressed in metastatic cancers and produces ammonia as a byproduct of its catalytic activity, is up-regulated by decreases in cellular pH and helps protect cells from acid-induced cell death. Since both TG2 and GLS1 can similarly function to protect cancer cells, we then proceeded to demonstrate that treatment of a variety of cancer cell types with inhibitors of each of these proteins results in synthetic lethality. The combination doses of the inhibitors induce cell death, while individual treatment with each compound shows little or no ability to kill cells. These results suggest that combination drug treatments that simultaneously target TG2 and GLS1 might provide an effective strategy for killing cancer cells.

A Tale of Two Glutaminases: Homologous Enzymes with Distinct Roles in Tumorigenesis

“…The GLS transcript has a pH-responsive element, which results in increased expression at acidic pH [104][105][106]. The transcription factor c-Myc indirectly upregulates GLS in some contexts by repressing the expression of miRNA-23 [96,107], which is also repressed by NF-κB [108].…”

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

“…Transglutaminase inhibition Combined inhibition of glutaminase and transglutaminase causes potentially lethal acidification 251 .…”

Targeting Glutamine Induces Apoptosis: A Cancer Therapy Approach

“…968 has specific effects on the growth, migration and invasive activity of transformed/cancer cells, and has no effects on the growth or morphology of their non-transformed cellular counterparts [ 91 , 93 ]. Growth of breast, brain and pancreatic cancer cells has been reported to be inhibited by 968 [ 131 ].…”

“…Interestingly, with activated mTORC1 signaling, combination of 968 and inhibitor of Hsp90, e.g., 17AAG increases apoptosis induced by 17AAG alone in Tsc2 −/− MEFs [ 130 ]. Simultaneous inhibition of GLS1 by 968 and tissue transglutaminase by inhibitor e.g., monodansylca-daverine, result in a synthetic lethality across a panel of assorted cancer cell lines [ 131 ]. The above-mentioned studies demonstrate that 968 is effective in not only inhibiting cancer cell growth, but also increasing cancer cells’ sensitivity to other chemotherapy drugs or other metabolic signaling inhibitors.…”