AMPK activation by AICAR sensitizes prostate cancer cells to radiotherapy

Abstract

Although radiotherapy is often used to treat localized disease and for palliative care in prostate cancer patients, novel methods are required to improve the sensitivity of aggressive disease to ionizing radiation. AMP-activated protein kinase (AMPK) is an energy sensor which regulates proliferation, aggressiveness and survival of cancer cells. We assessed the ability of the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) to sensitize prostate cancer cells to radiation. Prostate cancer cell lines LNCaP and PC3 were treated with X-rays and AICAR then assessed for clonogenic survival, spheroid growth delay, cell cycle progression, and AMPK and p53 activity. AICAR synergistically enhanced the clonogenic killing capacity, spheroid growth inhibition and pro-apoptotic effect of X-rays. The mechanism of radiosensitization appeared to involve cell cycle regulation, but not oxidative stress. Moreover, it was not dependent on p53 status. Treatment of PC3 cells with a fatty acid synthase inhibitor further enhanced clonogenic killing of the combination of X-rays and AICAR, whereas mTOR inhibition caused no additional enhancement. These results indicate that interference with metabolic signalling pathways which protect cells against irradiation have the potential to enhance radiotherapy. Activation of AMPK in combination with radiotherapy has the potential to target metabolically active and aggressive tumors which are currently untreatable.

Redox Homeostasis and Metabolism in Cancer: A Complex Mechanism and Potential Targeted Therapeutics

“…In acute and chronic myeloid leukemia (AML and CML, respectively), AICAR inhibited cellular proliferation, with induction of cell cycle arrest in G1-phase, and apoptosis through activation of the DNA damage-associated enzyme checkpoint kinase 1 (Chk1) induced by pyrimidine depletion [186], the activation of AMPK, and the inhibition of mTOR pathway in BCR-ABL and Philadelphia-positive acute lymphoblastic leukemia [190,191]. These results suggest that a possible combination of AICAR and an inhibitor of mTOR, such as rapamycin, or other PI3K/AKT/mTOR pathway inhibitors might be beneficial in the treatment of childhood leukemias (Figure 8), an AMP analog, is a purine biosynthesis precursor and a recognized agonist of AMPK that was found to cause a myriad of widespread metabolic alterations in various tumors [185,186]. Mechanistically, AICAR enters the cell through adenosine transporters and becomes phosphorylated by adenosine kinase into 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) [186].…”

“…5-Aminoimidazole-4-carboxamide ribonucleoside or acadesine (AICAR) (Figure 8), an AMP analog, is a purine biosynthesis precursor and a recognized agonist of AMPK that was found to cause a myriad of widespread metabolic alterations in various tumors [185,186]. Mechanistically, AICAR enters the cell through adenosine transporters and becomes phosphorylated by adenosine kinase into 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) [186].…”

MTHFD2 is a Metabolic Checkpoint Controlling Effector and Regulatory T Cell Fate and Function

“…In cancer cells, AICAR can have cytotoxic effects and increase sensitivity to chemotherapeutics and radiotherapy. These effects are often mediated by AMPK as AICAR is an adenosine analog and an established AMPK activator (Rae and Mairs, 2019;Su et al, 2019). Depending on the setting, however, AICAR may have AMPK-independent effects (Dembitz et al, 2019).…”

Cytotoxicity and Radiosensitizing Activity of the Fatty Acid Synthase Inhibitor C75 Is Enhanced by Blocking Fatty Acid Uptake in Prostate Cancer Cells

“…Differences between C75 and TVB-3166 may reflect modulation of different intracellular signalling pathways. C75 increases activation of the metabolic sensing AMP-activated kinase pathway, 37 which may also regulate sensitivity to radiation, 38 whereas TVB-3166 affects signalling by disrupting the lipid raft architecture. 22 In agreement with our findings with C75, decreasing monosaturated fatty acid availability by inhibition of the enzyme SCD1 decreased proliferation of breast cancer cells, and this effect was enhanced in low-serum condition and rescued by supplementation with oleic acid.…”