Role of hypoxia inducible factor-1 alpha in modulation of apoptosis resistance

Abstract

Hypoxia inducible factor-1 (HIF-1) is the major transcription factor and key regulator of adoptive responses to hypoxia. Although it usually promotes tumor cell survival under hypoxia, it has also been implied to trigger apoptosis. Although the impact of hypoxia has been extensively studied in many adult solid tumors, its role in most childhood tumors, for example, in rhabdomyosarcoma (RMS) or Ewing sarcoma (ES), has not yet been addressed. Here, we report that hypoxia protects A204 RMS and A673 ES cells against anticancer drug-or tumor necrosis factor-related apoptosis-inducing ligandinduced apoptosis and that Hif-1a plays a key role in conferring apoptosis resistance under hypoxia. Although a functional HIF-1 pathway and proapoptotic proteins such as p53 and Bcl-2/E1B 19 kDa interacting protein 3 were activated under hypoxia in both A204 RMS and A673 ES cells, these cells remained refractory to apoptosis. Concomitant analysis of antiapoptotic proteins revealed that hypoxia induced expression of Bcl-2 and inhibitor of apoptosis proteins (IAP)-2 as well as proteins associated with anaerobic metabolism such as the glucose transporter protein GLUT-1 and the glycolytic enzyme Aldolase A. Specific downregulation of Hif-1a by RNA interference significantly enhanced apoptosis under hypoxia by preventing the hypoxia-mediated increase in GLUT-1 expression without altering expression levels of the antiapoptotic proteins Bcl-2 or cIAP-2. Moreover, glucose deprivation-induced apoptosis of A204 RMS and A673 ES cells was inhibited under hypoxic conditions in a Hif-1a-dependent manner. As GLUT-1 was induced via Hif-1a under hypoxia in A204 RMS and A673 ES, these findings suggest that the Hif-1a-mediated increase in glucose uptake plays an important role in conferring apoptosis resistance. Thus, hypoxia-inducible genes may represent novel targets for therapeutic intervention in some pediatric tumors, which warrants further investigation.

Ursolic acid sensitized colon cancer cells to chemotherapy under hypoxia by inhibiting MDR1 through HIF-1α

“…For instance, HIF-1α is associated with enhanced apoptosis resistance (Kilic et al, 2007), while UA could promote apoptosis in many conditions and various types of cancer (Kashyap et al, 2016). Moreover, we also detected decreased apoptotic tumor cells by the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay under hypoxia, which could be reversed by UA (data not shown).…”

Effects of lentivirus-mediated HIF-1α knockdown on hypoxia-related cisplatin resistance and their dependence on p53 status in fibrosarcoma cells

“…Inhibition of glucose transport-1 expression and also drug resistancerelated proteins such as mdr1, mrp and lrp, and increased level of proapoptotic proteins such as Bid and Bax were ever reported to form the therapeutic basis of HIF-1 interference. 34,35 However, many factors might also limit the therapeutic efficacy of HIF-1 silencing. HIF-1a plays dual roles in the adaptive responses to hypoxia; 36,37 HIF-1 inhibition can have bimodal effects, proapoptotic or antiapoptotic, the relative dominance of which, together with environmental cues may ultimately determine the cell fate.…”

Physical and functional interaction of Runt-related protein 1 with hypoxia-inducible factor-1α

“…Angiogenesis, an essential process during development and diseases such as solid tumors, cardiovascular diseases and chronic inflammation (Folkman and Shing, 1992;Griffioen and Molema, 2000;Kilic et al, 2007), is induced by hypoxic condition, which is regulated by the hypoxia-inducible factor-1 (HIF-1) (Hirota and Semenza, 2006). This heterodimeric transcription factor is composed of the oxygen-sensitive HIF-1a and the constitutively presented HIF-1b subunits.…”