Poster Presentation 25th Lorne Cancer Conference 2013

Sensitivity to dichloroacetate is determined by PDK expression (#182)

Bevan P Gang 1 , Melissa Rooke 1 , Sheenu Mishra 2 , Jane Dalstrom 2 , Anneke C Blackburn 1
  1. Cancer Metabolism and Genetics Group, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
  2. ANU Medical School, The Australian National University, Canberra, ACT, Australia

The Warburg effect occurs in 90% of tumours, where there is a high rate of glycolysis even in the presence of oxygen. This results in increased lactate production and reduced pyruvate oxidation. Dichloroacetate (DCA) is used clinically for congenital lactic acidosis and can reverse the Warburg effect by inhibiting the pyruvate dehydrogenase kinases (PDKs), activating pyruvate dehydrogenase thus promoting oxidative metabolism of pyruvate. The PDKs have different sensitivities towards DCA inhibition (PDK2>PDK4>PDK1>>PDK3). We have investigated the effects of DCA on cancer growth in vivo and in vitro, and examined the expression of the PDK isoforms to explain variation of cancer cell responses to DCA.

DCA halted the growth of established V14 mouse mammary tumours in vivo, but was ineffective against 4T1 mouse mammary tumours. In 8 human cancer cell lines of breast, colon, pancreatic and prostate origin, 5 mM DCA (48 hr) inhibited growth by 5-40% in vitro. Western blotting for expression of PDK isoforms revealed that the most sensitive T-47D cells expressed PDK2 and low levels of the other PDKs, whereas less sensitive cells expressed high levels of PDK1 and/or PDK3. In siRNA knockdown (kd) experiments, PDK3-kd in MCF7 cells (low DCA sensitivity, high PDK3 levels) increased sensitivity to DCA by 30%, while DCA did not further inhibit growth of PDK2-kd T-47D cells, confirming that sensitivity to DCA growth inhibition is determined by the PDK profiles. PDK1 & 3 are up-regulated in hypoxia, which may reduce the effectiveness of DCA. To the contrary, DCA increased apoptosis in hypoxia in MCF7 cells, suggesting that DCA can enhance effects of other stressors/drugs, an area of ongoing investigation.

Use of the PDK profiles to target DCA sensitive tumours will improve the outcomes of clinical trials using DCA that are currently underway.