Phosphorylation-mediated activation of LDHA promotes cancer cell invasion and tumour metastasis.
Phosphorylation-mediated activation of LDHA promotes cancer cell invasion and tumour metastasis.
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作者：
Jin L;Chun J;Pan C;Alesi GN;Li D;Magliocca KR;Kang Y;Chen ZG;Shin DM;Khuri FR;Fan J;Kang S
转移仍然是癌症死亡的主要原因。最近的分子进展强调了癌细胞代谢变化的重要性，包括描述癌细胞糖酵解增加的华宝效应。然而，这种改变的新陈代谢如何促进肿瘤转移仍然难以捉摸。在这里，我们报告了磷酸化诱导的乳酸脱氢酶A(LDHA)的激活，这是一种催化丙酮酸和乳酸相互转化的酶，促进了癌细胞的侵袭、失巢耐药和肿瘤转移。我们证明LDHA是由上游的HER2和Src酶在酪氨酸10处磷酸化的。靶向HER2或Src可降低LDH活性以及头颈癌和乳腺癌细胞的侵袭潜能。小发夹状核糖核酸抑制LDH活性或表达缺磷LDHA Y10F使癌细胞对失巢凋亡敏感，并导致细胞侵袭减弱和活性氧增加，而这种表型可被其产物乳酸或抗氧化剂N-乙酰半胱氨酸逆转，提示Y10磷酸化介导的LDHA活性通过氧化还原稳态促进癌细胞侵袭和抗失巢凋亡。此外，LDHA基因敲除或LDHA Y10F在人类癌细胞中的救援性表达可减少异种移植小鼠的肿瘤转移。此外，在临床患者肿瘤样本中，LDHA在Y10的磷酸化与转移性乳腺癌的进展呈正相关。我们的发现表明，LDHA的磷酸化和激活为癌细胞提供了亲侵袭、抗失巢凋亡和促转移的优势，表明LDHA的Y10磷酸化可能是一个有前途的治疗靶点和转移性人类癌症的预后标志。
Metastases remain the major cause of death from cancer. Recent molecular advances have highlighted the importance of metabolic alterations in cancer cells, including the Warburg effect that describes an increased glycolysis in cancer cells. However, how this altered metabolism contributes to tumour metastasis remains elusive. Here, we report that phosphorylation-induced activation of lactate dehydrogenase A (LDHA), an enzyme that catalyses the interconversion of pyruvate and lactate, promotes cancer cell invasion, anoikis resistance and tumour metastasis. We demonstrate that LDHA is phosphorylated at tyrosine 10 by upstream kinases, HER2 and Src. Targeting HER2 or Src attenuated LDH activity as well as invasive potential in head and neck cancer and breast cancer cells. Inhibition of LDH activity by small hairpin ribonucleic acid or expression of phospho-deficient LDHA Y10F sensitized the cancer cells to anoikis induction and resulted in attenuated cell invasion and elevated reactive oxygen species, whereas such phenotypes were reversed by its product lactate or antioxidant N-acetylcysteine, suggesting that Y10 phosphorylation-mediated LDHA activity promotes cancer cell invasion and anoikis resistance through redox homeostasis. In addition, LDHA knockdown or LDHA Y10F rescue expression in human cancer cells resulted in decreased tumour metastasis in xenograft mice. Furthermore, LDHA phosphorylation at Y10 positively correlated with progression of metastatic breast cancer in clinical patient tumour samples. Our findings demonstrate that LDHA phosphorylation and activation provide pro-invasive, anti-anoikis and pro-metastatic advantages to cancer cells, suggesting that Y10 phosphorylation of LDHA may represent a promising therapeutic target and a prognostic marker for metastatic human cancers.
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影响因子：
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作者：
Alesi GN;Jin L;Li D;Magliocca KR;Kang Y;Chen ZG;Shin DM;Khuri FR;Kang S
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