Hypoxia-Inducible Factor-lα Increase is an Early and Sensitive Marker of Lung Cells Responding to Benzo[a]Pyrene

Abstract

Hypoxia inducible factor-1α (HIF-lα) is a central regulator of tumor survival and metastasis, responsible for metabolic adaptation to hypoxic conditions and promotion of angiogenesis. It has been also shown to respond to non-hypoxic stimuli, such as growth factors and moderate oxidative stress. We examined the protein levels of HIF-lα in A549 human lung cells exposed to the typical carcinogen benzo[a]pyrene (B[a]P). Our results revealed that B[a]P, at low, non-cytotoxic concentrations, induced a transient increase of nuclear HIF-lα and its target, GLUT1. HIF-lα upregulation was partly mediated by Akt kinase and coincided with increased nuclear levels of the redox-sensitive marker, nuclear factor erythroid 2-related factor-2 (NrF-2). B[a]P-induced HIF-lα was also detected during serum depletion or treatment with the hypoxia-mimicking agent, CoCl2. In addition, exposure of A549 cells to B[a]P containing diesel exhaust particles enhanced HIF-lα accumulation, probably due to the presence of additional carcinogenic compounds. B[a]P-induced increase of HIF-lα was further confirmed in normal rat and human lung fibroblasts. Our findings indicate that HIF-lα stimulation may act as an early and sensitive marker of exposure to low, non-cytotoxic concentrations of B[a]P and/or other carcinogens.

Enhanced Ca2+ Entry Sustains the Activation of Akt in Glucose Deprived SH-SY5Y Cells

“…HIF-1α is required for cellular protection and metabolic alterations and, as such, is considered one of the many downstream targets of Akt. We and several other groups have established that under conditions that promote cell survival, there is a dose-dependent increase in both the protein levels of HIF-1α and p-Akt [34,[40][41][42]. In addition, previous results of our group indicate that a partial connection between these two proteins takes place even under specific stressful conditions, i.e., in the presence of the carcinogenic benzo [α] pyrene [42].…”

“…We and several other groups have established that under conditions that promote cell survival, there is a dose-dependent increase in both the protein levels of HIF-1α and p-Akt [34,[40][41][42]. In addition, previous results of our group indicate that a partial connection between these two proteins takes place even under specific stressful conditions, i.e., in the presence of the carcinogenic benzo [α] pyrene [42]. Here, a similar connection was also proved both during glucose deprivation and in the presence of CoCl 2.…”

Differential effects of calcium on PI3K-Akt and HIF-1α survival pathways

“…Data are the mean ± SEM of at least three independent experiments. *P < 0.05, **P < 0.01, and † P < 0.001 compared with control between these two proteins was detected even under specific stressful conditions, i.e., in the presence of the carcinogenic benzo[α]pyrene (Mavrofrydi and Papazafiri 2012) or volatile anesthetics (Benzonana et al 2013;Huang et al 2014;Iwasaki et al 2016). Here, we present evidence of a crosstalk between pAkt and HIF-1α during calcium homeostasis disturbances.…”

Filling the gap between chemical carcinogenesis and the hallmarks of cancer: A temporal perspective

“…51 Similarly, low, noncytotoxic concentration of BaP induced hypoxia-inducible factor-1a, responsible for the adaptation to hypoxic conditions and the promotion of angiogenesis. 52 Interestingly, BaP and its metabolites may have distinct and opposite effect on VEGF expression, 53 suggesting that tissue-specific or genetic interindividual differences in the CYP450 expression may play a role in determining the overall effect on angiogenesis induction by BaP and PAHs in general.…”