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Non‐glycolytic Function of Aldolase A Promotes Lung Cancer Metastasis through Down‐regulation of PLD2 Enzyme to Activate PLD1

In cancer, glycolysis rate is increased regardless of the oxygen availability, a phenomenon known as the Warburg effect. Several enzymes in glycolytic pathway have been investigated as potential therapeutic targets for cancer. However, the impact of targeting each glycolytic enzyme for cancer treatment remains unclear. Here, we perform systemic RNAi and pharmacological screening targeting every glycolysis pathway enzyme in lung cancer to found aldolase A (ALDOA) knockdown most significantly inhibits cell invasion/migration. However, this effect was not due to aldolase enzyme activity inhibition. Moreover, ALDOA knockdown does not affect glucose consumption, lactate production or intracellular ATP concentration, indicating a non‐glycolytic cause for lung cancer invasion/migration inhibition. We further perform immunoprecipitation and mass spectrometry using ALDOA as a bait in invasive lung cancer cells and found phospholipase D (PLD) and several ALDOA‐interacting proteins that may affect cancer invasion and metastasis. We further identify ALDOA interacts with Phospholipase D2 (PLD2) through PH domain and inhibits its enzyme activity. Instead, PLD1 upregulated to compensate the PLD enzyme activity and phosphatidic acid (PA) production to activate beta‐catenin/TCF‐4 signaling axis that are essential for ALDOA induced lung cancer cell invasion/metastasis. Taken together, our results uncover a novel non‐glycolytic function of ALDOA to promote lung cancer metastasis via PLD2 interaction and PLD1 activation that provides new mechanistic insights into lung carcinogenesis, with implication of novel strategy for lung cancer treatment.