Therapeutic metformin/AMPK activation blocked lymphoma cell growth via inhibition of mTOR pathway and induction of autophagy

Abstract

Adenosine monophosphate-activated protein kinase (AMPK) acts as a major sensor of cellular energy status in cancers and is critically involved in cell sensitivity to anticancer agents. Here, we showed that AMPK was inactivated in lymphoma and related to the upregulation of the mammalian target of rapamycin (mTOR) pathway. AMPK activator metformin potentially inhibited the growth of B- and T-lymphoma cells. Strong antitumor effect was also observed on primary lymphoma cells while sparing normal hematopoiesis ex vivo. Metformin-induced AMPK activation was associated with the inhibition of the mTOR signaling without involving AKT. Moreover, lymphoma cell response to the chemotherapeutic agent doxorubicin and mTOR inhibitor temsirolimus was significantly enhanced when co-treated with metformin. Pharmacologic and molecular knock-down of AMPK attenuated metformin-mediated lymphoma cell growth inhibition and drug sensitization. In vivo, metformin induced AMPK activation, mTOR inhibition and remarkably blocked tumor growth in murine lymphoma xenografts. Of note, metformin was equally effective when given orally. Combined treatment of oral metformin with doxorubicin or temsirolimus triggered lymphoma cell autophagy and functioned more efficiently than either agent alone. Taken together, these data provided first evidence for the growth-inhibitory and drug-sensitizing effect of metformin on lymphoma. Selectively targeting mTOR pathway through AMPK activation may thus represent a promising new strategy to improve treatment of lymphoma patients.

mTOR: a pharmacologic target for autophagy regulation

“…Therefore, since active AMPK promotes autophagy by phosphorylating key autophagy regulatory proteins such as ULK1, VPS34, and Beclin 1 (70,72), metformin can induce autophagy by simultaneously activating AMPK and inhibiting mTORC1. Consequently, metformin-induced autophagy and its beneficial effects have been demonstrated in various cancer cells in vitro as well as in in vivo models (114)(115)(116)(117)(118). tion using a rapamycin-FKBP12 complex and by yeast two-hybrid analysis (88)(89)(90)(91).…”

Autophagy in Vascular Disease

“…Metformin, on the contrary, is a standard drug for the treatment of type 2 diabetes mellitus, and has been shown to attenuate neointima formation by inhibiting SMC proliferation, migration, and inflammation. Metformin stimulates autophagy via AMPK, which impairs tumor progression, 123,124 but it remains to be determined whether the macrovascular effects of metformin in diabetes mellitus are autophagy dependent.…”

Acute metformin preconditioning confers neuroprotection against focal cerebral ischaemia by pre‐activation of AMPK‐dependent autophagy

“…Several lines of evidence suggest that autophagy can be induced by metformin via an AMPK-dependent manner in peripheral tissues. For example, metformin induces autophagy by activating AMPK in a wide variety of malignant tumours (Harhaji-Trajkovic et al, 2009;Shi et al, 2012). More importantly, acute preconditioning with a single dose of metformin was shown to induce AMPK-mediated autophagy in the heart, which subsequently conferred protection against cardiac dysfunction following diabetes or myocardial ischaemia (Calvert et al, 2008).…”