RESUMEN
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.
Asunto(s)
Neoplasias de la Mama/enzimología , L-Lactato Deshidrogenasa/metabolismo , Procesamiento Proteico-Postraduccional , Animales , Anoicis/efectos de los fármacos , Antineoplásicos/farmacología , Benzodioxoles/farmacología , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular , Activación Enzimática , Femenino , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , L-Lactato Deshidrogenasa/genética , Lactato Deshidrogenasa 5 , Metástasis Linfática , Ratones Desnudos , Invasividad Neoplásica , Trasplante de Neoplasias , Fosforilación , Quinazolinas/farmacología , Especies Reactivas de Oxígeno , Receptor ErbB-2/metabolismo , Familia-src Quinasas/metabolismoRESUMEN
Metastasis is responsible for >90% of cancer-related deaths. Complex signaling in cancer cells orchestrates the progression from a primary to a metastatic cancer. However, the mechanisms of these cellular changes remain elusive. We previously demonstrated that p90 ribosomal S6 kinase 2 (RSK2) promotes tumor metastasis. Here we investigated the role of RSK2 in the regulation of microtubule dynamics and its potential implication in cancer cell invasion and tumor metastasis. Stable knockdown of RSK2 disrupted microtubule stability and decreased phosphorylation of stathmin, a microtubule-destabilizing protein, at serine 16 in metastatic human cancer cells. We found that RSK2 directly binds and phosphorylates stathmin at the leading edge of cancer cells. Phosphorylation of stathmin by RSK2 reduced stathmin-mediated microtubule depolymerization. Moreover, overexpression of phospho-mimetic mutant stathmin S16D significantly rescued the decreased invasive and metastatic potential mediated by RSK2 knockdown in vitro and in vivo. Furthermore, stathmin phosphorylation positively correlated with RSK2 expression and metastatic cancer progression in primary patient tumor samples. Our finding demonstrates that RSK2 directly phosphorylates stathmin and regulates microtubule polymerization to provide a pro-invasive and pro-metastatic advantage to cancer cells. Therefore, the RSK2-stathmin pathway represents a promising therapeutic target and a prognostic marker for metastatic human cancers.
Asunto(s)
Neoplasias Pulmonares/genética , Metástasis de la Neoplasia/genética , Proteínas Quinasas S6 Ribosómicas 90-kDa/genética , Estatmina/genética , Células A549 , Movimiento Celular/genética , Técnicas de Silenciamiento del Gen , Humanos , Neoplasias Pulmonares/patología , Microtúbulos/genética , Microtúbulos/patología , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Metástasis de la Neoplasia/patología , Fosforilación , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Transducción de Señal , Estatmina/metabolismoRESUMEN
Cancer cells display an altered metabolic circuitry that is directly regulated by oncogenic mutations and loss of tumor suppressors. Mounting evidence indicates that altered glutamine metabolism in cancer cells has critical roles in supporting macromolecule biosynthesis, regulating signaling pathways, and maintaining redox homeostasis, all of which contribute to cancer cell proliferation and survival. Thus, intervention in these metabolic processes could provide novel approaches to improve cancer treatment. This review summarizes current findings on the role of glutaminolytic enzymes in human cancers and provides an update on the development of small molecule inhibitors to target glutaminolysis for cancer therapy.