Fig. 4.

PERK/UPR and HIF deficiency delays tumor formation. (A) Tumor growth of s.c. implanted isogenic HCT116 cells targeting HIF-1α (i.e., shHIF-1α), GADD34c, and control cells [pCDNA5(+)] preexposed (24 h) to doxycycline (dox) were injected into doxycycline receiving nude mice [mean ± SEM, pCDNA5(+), n = 6; GADD34c, n = 8; shHIF-1α, n = 8]. (B) Palpability (>60 mm³) of tumors. (C) Doubling time of individual tumors. (D) After establishment (150 mm³), mice received doxycycline in their drinking water [mean ± SEM; pCDNA5(+), n = 10; GADD34c, n = 7; shHIF-1α, n = 10]. (E) Doubling time of the individual tumors. (F) Tumors were harvested after 7 d doxycycline, and hypoxia was assessed by pimonidazole immunohistochemistry of the viable tumor tissue. (G) Mice with established tumors (150 mm³) received doxycycline in drinking water. Growth (dotted lines) and regrowth after irradiation (t = 0) was followed over time in animals that received no doxycycline (−dox, n = 7) or doxycycline from day −4 to day +3 [+dox 7 d (10 Gy), n = 8] or doxycycline after irradiation [+dox after irradiation (10 Gy), n = 10]. (H) Kaplan–Meier survival for tumors in Fig. 4 D and G to with the endpoint of reaching four times the initial volume.