Pyruvate kinase appears to be bladder cancer marker

Pyruvate kinase, a primary driver of tumor glycolysis, is promising both as a biomarker of bladder cancer and as a drug target, researchers reported at the 2018 Society of Urologic Oncology annual meeting in Phoenix.

Growing bladder cancer cells in increasing concentrations of glucose resulted in upregulation in the expression of tumor M2-PK, the dimeric form of the pyruvate kinase M2 isoenzyme, according to the researchers.

Moreover, exposing bladder cancer cell lines to a pyruvate kinase inhibitor reduced cell proliferation and caused switching of pyruvate kinase isoforms, said researcher Eugene K. Lee, MD, assistant professor of urology in the division of urologic oncology at the University of Kansas Medical Center, Kansas City.

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Although these are early findings, they do suggest potential implications for evaluation and treatment of bladder cancer at some point in the future, Dr. Lee said in an interview with Urology Times.

“Clearly, metabolism is important for bladder cancer, so I do think that we could potentially use this as a urinary marker-either as an adjunct to cystoscopy, or potentially as an alternative to cystoscopy, which would be an ideal goal, though I think that we’re far from that,” he said.

Bladder cancer cells have a high affinity for glucose and depend on a shift to aerobic glycolysis-dependent metabolism, which is known as the Warburg effect, and pyruvate kinase is a principal driver of that effect, investigators said.

Pyruvate kinase M2 oscillates between an inactive dimer, which predominates in bladder cancer, and active tetrameter, they noted.

In their research, presented as a poster at the SUO annual meeting, Dr. Lee and co-investigators exposed two bladder cancer cell lines after exposure to varying concentrations of glucose, and then assessed cell proliferation and protein expression of pyruvate kinase M2.

Significant increases in cell proliferation and upregulation of pyruvate kinase M2 expression were seen when they exposed cells to higher glucose levels, they reported.

Compared to the standard 100-mg/dL glucose level, a 200-mg/dL level resulted in a twofold increase in growth rate for UM-UC-3 cells (urinary bladder transitional cell carcinoma) cells, and a 1.7-fold increase in HTB-9 cells (urinary bladder, grade II carcinoma).

Conversely, when glucose was reduced to 25 mg/dL, there was a 3.75-fold decrease in growth rate in UM-UC-3 cells and a 2.8-fold decrease in HTB-9 cells, the data show.

Next: Shikonin also evaluatedShikonin also evaluated

Dr. Lee and colleagues also evaluated the effects of shikonin, a pyruvate kinase inhibitor, in inhibiting cancer cell proliferation at various glucose concentrations.

Shikonin treatment not only inhibited cell proliferation, they found, but resulted in switching of the pyruvate kinase M2 isoforms from the bladder cancer-associated dimeric form (M2-PK) to the tetrameter form.

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In patient samples, dimeric tumor M2-PK has been significantly correlated with presence of bladder cancer, the investigators noted.

The poster was presented by co-investigator Meredith Metcalf, MD, of the University of Kansas.