Abstract
PRL-3, a metastasis-associated phosphatase, is known to exert its oncogenic functions through activation of PI3K/Akt, which is a key regulator of the rapamycin-sensitive mTOR complex 1 (mTORC1), but a coherent link between PRL-3 and activation of mTOR has not yet been formally demonstrated. We report a positive correlation between PRL-3 expression and mTOR phospho-activation in clinical tumour samples and mouse models of cancer and demonstrate that PRL-3 increased downstream signalling to the mTOR substrates, p70S6K and 4E-BP1, by increasing PI3K/Akt-mediated activation of Rheb-GTP via TSC2 suppression. We also show that PRL-3 increases mTOR translocation to lysosomes via increased mTOR binding affinity to Rag GTPases in an Akt-independent manner, demonstrating a previously undescribed mechanism of action for PRL-3. PRL-3 also enhanced matrix metalloproteinase-2 secretion and cellular invasiveness via activation of mTOR, attributes which were sensitive to rapamycin treatment. The downstream effects of PRL-3 were maintained even under conditions of environmental stress, suggesting that PRL-3 provides a strategic survival advantage to tumour cells via its effects on mTOR.
Highlights
We further investigated the above finding in the spontaneous mouse mammary tumour virus (MMTV) transgenic model, which harbours the polyomavirus middle T oncoprotein (PyMT) under transcriptional control of the MMTV promoter-enhancer, resulting in the formation of palpable mammary tumours in mice as early as 6 weeks of age[26]
We found that PRL-3 overexpression induces an aberrant activation of mechanistic target of rapamycin (mTOR) kinase in cancer cells, as reflected by hyperphosphorylation of the direct substrates of mTOR complex 1 (mTORC1), 4E (eIF4E)-binding protein 1 (4E-BP1) and p70 S6 kinase (p70S6K)
We formally demonstrate the signalling pathway by which PRL-3 induces mTORC1 activation as via the Akt-TSC2-Rheb signalling pathway
Summary
Full mTORC1 activation is a two-pronged process, requiring growth factor signalling (via PI3K/Akt) to activate Rheb, and mTORC1 translocation to Rheb-resident endomembranes, lysosomes[11]. Through the activation of upstream RTKs, PRL-3 enhances cell growth and survival through multiple oncogenic effector pathways, including PI3K/Akt, Ras/MAPK, and SRC17–19. Given that cells overexpressing PRL-3 exhibit shared characteristics with cells possessing hyperactive PI3K/Akt/mTOR signalling, including enhanced cell proliferation, survival, and motility, we hypothesized that PRL-3 might potentially play a role in mTOR regulation, as well in cancer progression. PRL-3 was shown previously to promote autophagy in ovarian cancers[23], a phenomenon typically inhibited by mTOR activity[24] This observation was later shown to be rapamycin-insensitive, discounting a role for mTORC1 as a proxy for PRL-3-driven autophagy. Our results uncover a role for oncogenic PRL-3 signalling via mTORC1 both in vivo and in vitro
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