Hypoxia tolerance of cancer cells through suppression of mTOR signaling

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mTOR (mammalian target of rapamycin) is activated and contributes to proliferation and survival of cancer cells under oxygenated and nutritionally rich conditions. On the other hand, under hypoxic and nutritionally poor conditions, mTOR signal is suppressed, although the physiological role of the suppression had not been clarified. This study aimed at elucidating the correlation between the suppression of mTOR signaling and cancer cell survival under hypoxic conditions.First, we examined the molecular mechanism in vitro. In a colon cancer cell line, COLO 320, which is hypoxia sensitive, over-expression of Rheb as well as eIF4E activated mTOR signaling even under hypoxic conditions. Rheb and eIF4E introduced cells were more sensitive to hypoxia. The death was circumvented by inhibition of PI3K or mTOR. On the other hand, in a pancreas cancer cell line, AsPC-1, which is hypoxia tolerant, neither rheb nor eIF4E could activate mTOR signaling under hypoxic conditions. We also tried TAT-ODD system equipped with active form of Rheb. AsPC-1 cells treated with TAT-ODD-rheb could not stimulate mTOR signaling under hypoxic conditions. Together, in AsPC-1 cells, other factors in addition to rheb are necessary to activate mTOR signaling under hypoxic conditions.We found that IGF stimulation generated massive apoptosis in COLO 320 cells in hypoxia as well as AsPC-1 cells in anoxia. IGF induced robust endoplasmic reticulum stress, ER stress, under hypoxic conditions, and the ER stress was necessary for apoptosis. Especially, we revealed that CHOP induction was critical for the cell death (Cancer Research, in revision). We also found that phosphorylation of S6, a downstream event of mTOR activation, was suppressed under hypoxic area compared with well oxygenized area. Since, we could not activate mTOR signaling under hypoxic area in vivo, the role of mTOR suppression in vivo remains to be elucidated.