Abstract
The mammalian target of rapamycin (mTOR) functions as two complexes (mTORC1 and mTORC2), regulating cell growth and metabolism. Aberrant mTOR signaling occurs frequently in cancers, so mTOR has become an attractive target for cancer therapy. Iron chelators have emerged as promising anticancer agents. However, the mechanisms underlying the anticancer action of iron chelation are not fully understood. Particularly, reports on the effects of iron chelation on mTOR complexes are inconsistent or controversial. Here, we found that iron chelators consistently inhibited mTORC1 signaling, which was blocked by pretreatment with ferrous sulfate. Mechanistically, iron chelation-induced mTORC1 inhibition was not related to ROS induction, copper chelation, or PP2A activation. Instead, activation of AMPK pathway mainly and activation of both HIF-1/REDD1 and Bnip3 pathways partially contribute to iron chelation-induced mTORC1 inhibition. Our findings indicate that iron chelation inhibits mTORC1 via multiple pathways and iron is essential for mTORC1 activation.
Highlights
The mechanistic/mammalian target of rapamycin, a serine/threonine kinase, plays critical roles in regulating cell growth, proliferation, survival, and motility through sensing environmental cues. mTOR functions as two complexes, mTORC1 and mTORC2 [1, 2]. mTORC1 contains mTOR, mLST8 (mammalian let, raptor [3,4,5]), and PRAS40
The results showed that all cancer cell lines were sensitive to Ciclopirox Olamine (CPX) and Dp44mT, but all normal cell lines were highly resistant to the two compounds (Fig. 1a, b)
We demonstrated that iron chelation consistently inhibited mTORC1 in multiple cancer cells, but not in normal cells (PCS-201-012, C2C12 and L6) using iron chelators, CPX, Dp44mT, or DFO (Figs. 1e–g and S1)
Summary
The mechanistic/mammalian target of rapamycin (mTOR), a serine/threonine kinase, plays critical roles in regulating cell growth, proliferation, survival, and motility through sensing environmental cues. mTOR functions as two complexes, mTORC1 and mTORC2 [1, 2]. mTORC1 contains mTOR, mLST8 (mammalian let, raptor (regulatory-associated protein of mTOR) [3,4,5]), and PRAS40 (proline-rich Akt substrate 40). Activation of mTORC1 promotes anabolic processes involved in cell growth and metabolism. Akt-induced TSC1/2 dissociation impedes the negative regulation of TSC1/2 on Rheb, activating mTORC1 [15,16,17,18]. Under energy stress, AMPK (AMP-activated protein kinase) is activated, which phosphorylates raptor on S792, inhibiting the activity of mTORC1 [23]. AMPK inhibits mTORC1 through phosphorylating TSC2 and activating the TSC1/2 complex [24]. Studies have found that expression levels of iron regulating proteins, such as transferrin receptor are altered in cancer cells, leading to increased intracellular iron level [28,29,30]. This study was set to determine whether and how iron chelation inhibits mTOR signaling
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