PAX9 reactivation by inhibiting DNA methyltransferase triggers antitumor effect in oral squamous cell carcinoma.

Aberrant DNA hypermethylation is associated with oral carcinogenesis. Procaine, a local anesthetic, is a DNA methyltransferase (DNMT) inhibitor that activates anticancer mechanisms. However, its effect on silenced tumor suppressor gene (TSG) activation and its biological role in oral squamous cell carcinoma (OSCC) remain unknown. Here, we report procaine inhibited DNA methylation by suppressing DNMT activity and increased the expression of PAX9, a differentiation gene in OSCC cells. Interestingly, the reactivation of PAX9 by procaine found to inhibit cell growth and trigger apoptosis in OSCC in vitro and in vivo. Likely, the enhanced PAX9 expression after exposure to procaine controls stemness and differentiation through the autophagy-dependent pathway in OSCC cells. PAX9 inhibition abrogated procaine-induced apoptosis, autophagy, and inhibition of stemness. In OSCC cells, procaine improved anticancer drug sensitivity through PAX9, and its deficiency significantly blunted the anticancer drug sensitivity mediated by procaine. Additionally, NRF2 activation by procaine facilitated the antitumor response of PAX9, and pharmacological inhibition of NRF2 by ML385 reduced death and prevented the decrease in the orosphere-forming potential of OSCC cells. Furthermore, procaine promoted antitumor activity in FaDu xenografts in athymic nude mice, and immunohistochemistry data showed that PAX9 expression was significantly enhanced in the procaine group compared to the vehicle control. In conclusion, PAX9 reactivation in response to DNMT inhibition could trigger a potent antitumor mechanism to provide a new therapeutic strategy for OSCC.

The E-Cadherin and N-Cadherin Switch in Epithelial-to-Mesenchymal Transition: Signaling, Therapeutic Implications, and Challenges.

Epithelial-to-Mesenchymal Transition (EMT) has been shown to be crucial in tumorigenesis where the EMT program enhances metastasis, chemoresistance and tumor stemness. Due to its emerging role as a pivotal driver of tumorigenesis, targeting EMT is of great therapeutic interest in counteracting metastasis and chemoresistance in cancer patients. The hallmark of EMT is the upregulation of N-cadherin followed by the downregulation of E-cadherin, and this process is regulated by a complex network of signaling pathways and transcription factors. In this review, we summarized the recent understanding of the roles of E- and N-cadherins in cancer invasion and metastasis as well as the crosstalk with other signaling pathways involved in EMT. We also highlighted a few natural compounds with potential anti-EMT property and outlined the future directions in the development of novel intervention in human cancer treatments. We have reviewed 287 published papers related to this topic and identified some of the challenges faced in translating the discovery work from bench to bedside.

The role of pro-inflammatory molecules and pharmacological agents in acute pancreatitis and sepsis.

Acute pancreatitis (AP) and sepsis are inflammatory disorder varying in magnitude of response to infection or inflammatory stimuli. The specific role of various causative factors in AP, septic shock, current pharmacological treatments, animal models, role of infiltrating cells and novel molecules that play an important role in the disease progression to sepsis are explored. AP is an inflammatory disease of the pancreas. Over the years accumulating evidence suggests numerous molecules as key regulators of the inflammatory signaling cascade such as selectins, chemokine signaling and expression of intergrins on leukocytes facilitate adhesion to vessel walls. Inhibition of any of these molecules has proven to be effective in animal models of AP. Recently, the biochemical role of hydrogen sulfide (H(2)S) and substance P in caerulein induced AP and in cecal ligation and puncture induced sepsis and their role in the pathogenesis of the disease have highlighted the importance of novel molecules as therapeutic targets in addition to the known pro-inflammatory molecules, cytokines and chemoattractant chemokines and their receptors upregulated in AP and sepsis. This review aims to give an overview of the multifaceted complex interactions in a prearranged fashion and their functional role in the inflammatory process that afflict AP and sepsis. The interlinking molecules in AP and sepsis emphasize the similarities in the inflammatory response and the importance of pharmacological agents that reduce or inhibit the progression to chronic stage.