Novel therapies targeting hypoxia mechanism to treat pancreatic cancer

Abstract

Pancreatic cancer (PC) is one of the deadliest malignancies. The high mortality rate of PC largely results from delayed diagnosis and early metastasis. Therefore, identifying novel treatment targets for patients with PC is urgently required to improve survival rates. A major barrier to successful treatment of PC is the presence of a hypoxic tumor microenvironment, which is associated with poor prognosis, treatment resistance, increased invasion and metastasis. Recent studies have identified a number of novel molecules and pathways in PC cells that promote cancer cells progression under hypoxic conditions, which may provide new therapy strategies to inhibit the development and metastasis of PC. This review summarizes the latest research of hypoxia in PC and provides an overview of how the current therapies have the capacity to overcome hypoxia and improve PC patient treatment. These findings will eventually provide guidance for future PC management and clinical trials and hopefully improve the survival of patients with PC.

Keywords: Pancreatic cancer; hypoxia; novel strategies; survival; tumor microenvironment.

Figure 1

Mechanisms of novel strategies targeting PSCs and hypoxia environment. Activated PSCs show increased expressions of collagen-I and α-smooth muscle actin, which are important for cancer progression and metastasis. Activated PSCs also secrete IL-6, stromal cell-derived factor-1 and transforming growth factor-β, which are associated with tumor progression and metastasis. A study demonstrated that HIF-1α increases the secretion of C-C motif chemokine ligand 2 to recruit macrophages, accelerating the activation of PSCs. Hypoxia can induce PSCs to secrete IL-6, which in turn promotes the progression of pancreatic cancer through the JAK2/STAT3 and mitogen-activated protein kinase pathways. Curcumin inhibits the tumor-stromal crosstalk by inhibiting the IL-6/ERK/NF-κB pathway, and activation of PSCs is inhibited by curcumin under hypoxic conditions. PSC, pancreatic stellate cell; IL, interleukin; HIF, hypoxia-inducible factor; CXCL2, chemokine 2; SDF-1, stromal cell derived factor-1.

Figure 2

Mechanisms of novel strategies targeting IL-37, RER1 and RAD51 under hypoxic environment. 1) HIF-1α directly binds to HREs which as a result reduced IL-37 transcription in PC. Moreover, IL-37 can suppress HIF-1α expression through STAT3 inhibition; 2) RER1 induces the development of PC via enhancing EMT and CSC pathway. RER1 can induce PC cells to convert to CSCs. Moreover, HIF-1α can increase RER1 expression, and hypoxia-induced PC cell progression may be activated by RER1 with the help of HIF-1α; 3) RAD51 positively regulated cell proliferation, decreased intracellular ROS production and increased the HIF-1α protein level. KRAS/MEK/ERK activation increased RAD51 expression; 4) PC modulate the CA9 to regulate pH. CA9 is a down-stream of mutant KRAS. Intra-tumoral hypoxia leads to HIF-1α-mediated metabolic regulation by PC and the production of acidic metabolites. Glycolysis can create an acidic microenvironment via lactate accumulation, resulting in extracellular matrix destruction that favors metastasis. IL, interleukin; RER1, retention in endoplasmic reticulum 1; RAD51, recombination protein A D51; HIF, hypoxia-inducible factor; HRE, hypoxia-response element; PC, pancreatic cancer; CSC, cancer stem cell; ROS, reactive oxygen species; CA 9, carbonic anhydrase 9.

Figure 3

Mechanisms of novel strategies targeting miRNAs and EMT under hypoxia condition. 1) miR-224 inversely regulated TXNIP by binding directly it, activating HIF-1α as a result. The CRM1 region of TXNIP binds the nuclear transcription factor HIF-1α and the ubiquitin ligase pVHL. The TXNIP-pVHL-HIF-1α complex results in the degradation of HIF-1α; 2) TP63 was a direct target of miR-301a and involved in the metastatic process of PC cells via up-regulation of epithelial marker E-cadherin and the down-regulation of mesenchymal marker vimentin; 3) Over-expression of miR-210 can decrease the E-cadherin and b-catenin as well as HOXA9 level and increase vimentin and N-cadherin; 4) WNT7A is a vital ligand to activate the Wnt/β-catenin pathway. WNT7A expression promotes higher expression of N-cadherin and lower expression of E-cadherin; 5) DKK-3 inhibits EMT of PC cells in hypoxic conditions by suppressing the translocation of b-catenin to nucleus, resulting in enhancing of the antitumor effects to PC. EMT, epithelial-to-mesenchymal transition; TXNIP, thioredoxin-interacting protein; HIF, hypoxia-inducible factor; DKK-3, dickkopf-related protein 3.

Figure 4

Mechanisms of novel strategies targeting signaling pathway and mitochondrial abnormalities under hypoxia condition. (1) Under hypoxia, MTA1 increased the expression of HIF-α and VEGF proteins; (2) EGFR/ERK/HIF-1α can be activated by hypoxic conditions. PHD3 can degrade HIF-1α in the hypoxic microenvironment of PC; (3) Hypoxia induced STK33 expression in PC cells. HIF-1α regulated STK33 via direct binding to a hypoxia response element in its promoter; (4) HIF-1α directly increased the expression of PAFAH1B2 by binding to an HRE on PAFAH1B2 promoter in PC cells; (5) PGC-1α activates NRF-1 and then up-regulates TFAM expression. HMGB1 can up-regulate the protein expression of PGC-1α, and then activate AMPK. AMPK can regulate mitochondrial biogenesis by increasing SIRT1 and inducing PGC-1 deacetylation; (6) SIRT4 is a downstream target of Ubiquitin like with plant homeodomain and ring finger domains 1 (UHRF1) and negatively correlated with UHRF1, which can suppress HIF-1α; (7) PSK can not only inhibit SMO but also reduce mastermind-like 3 and recombination signal binding protein for immunoglobulin-kappa-J region (RBPJ) expression in PC cells under hypoxia. Hh signaling can be activated by increasing the transcription of SMO gene under hypoxia. Another mechanism is that RBPJ forms a complex with the NICD that is stabilized by MAML3, and Notch signaling is activated by binding of the RBPJ/NICD/MAML3 complex to DNA in the nucleus. Hes1-3, a target gene of Notch signaling, can be decreased by RBPJ and MAML3 inhibition. RBPJ and MAML3 inhibition under hypoxia led to decreased SMO. MTA1, metastasis-associated gene 1; HIF, hypoxia-inducible factor; VEGF, vascular endothelial growth factor; EGFR, epidermal growth factor receptor; PC, pancreatic cancer; STK 33, serine/threonine kinase 33; PAFAH1B2, platelet-activating factor acetylhydrolase IB subunit beta; NRF, nuclear respiratory factor; TFAM, mitochondrial transcription factor A; HMGB1, High-mobility group box-1; AMPK, AMP-activated protein kinase; SMO, smoothened; Hh, Hedgehog; MAML3, mastermind-like 3.