NNK from tobacco smoking enhances pancreatic cancer cell stemness and chemoresistance by creating a β2AR‐Akt feedback loop that activates autophagy

Abstract

Low responsiveness to chemotherapy is an important cause of poor prognosis in pancreatic cancer. Smoking is a high‐risk factor for pancreatic cancer and cancer resistance to gemcitabine; however, the underlying mechanisms remain unclear. 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone (NNK) is the main metabolite of tobacco burning and has been shown to be associated with cancer development and chemoresistance. However, in pancreatic cancer, its mechanism remains poorly understood. In this study, we found that NNK promoted stemness and gemcitabine resistance in pancreatic cancer cell lines. Moreover, NNK increased autophagy and elevated the expression levels of the autophagy‐related markers autophagy‐related gene 5 (ATG5), autophagy‐related gene 7 (ATG7), and Beclin1. Furthermore, the results showed that NNK‐promoted stemness and gemcitabine resistance was partially dependent on the role of NNK in cell autophagy, which is mediated by the β2‐adrenergic receptor (β2AR)‐Akt axis. Finally, we proved that NNK intervention could not only activate β2AR, but also increase its expression, making β2AR and Akt form a feedback loop. Overall, these findings show that the NNK‐induced β2AR‐Akt feedback loop promotes stemness and gemcitabine resistance in pancreatic cancer cells.

miRNA signatures underlie chemoresistance in the gemcitabine-resistant pancreatic ductal adenocarcinoma cell line MIA PaCa-2 GR

“…To further refine this dataset, we considered risk factors (gray, Figure 7 ) associated with PDAC. This was done to further focus on the most aggressive factors associated with PDAC, as these risk factors have been associated with increased cancer aggressiveness and chemoresistance ( Incio et al, 2016 ; Chen et al, 2022 ; Kesh et al, 2022 ; Vaziri-Gohar et al, 2023 ). To pair this with the DEmiR set, we assembled an miRNA list from the keywords: “nicotine consumption/nicotine addiction,” “diabetes,” “obesity,” “pancreatitis,” “acute pancreatitis,” “chronic pancreatitis,” and “metabolic syndrome,” The list provided 372 unique miRNAs that shared 17 factors with the DEmiR set.…”

A Novel Mechanism of 16α-OHE1, One of Estrogen Metabolites, Alleviating Inflammatory Infiltration in Hypoxia-Induced Myocardial Injury via β2-Adrenergic Receptor

“…We hypothesize that the protective effect of 16α-OHE1 against hypoxia-induced myocardial injury may be related to β 2 AR activation. To explore this mechanism, we used the β 2 AR blocker ICI 118,551 to determine whether the myocardial protective effect of 16α-OHE1 was affected by impairing β 2 AR signaling, following previous experience [48][49][50] . As expected, when β 2 AR signaling is blocked, the antiapoptotic and cell viabilityenhancing effects of 16α-OHE1 on hypoxia-induced H9C2 cells disappeared.…”

Smoking induces WEE1 expression to promote docetaxel resistance in esophageal adenocarcinoma

“… 18 , 20 , 32 , 40 According to recent publications, smoking promotes drug resistance in multiple human cancers, including the lung, prostate, and pancreas. 41 , 42 , 43 Since WEE1 was induced by smoking in EAC, we tested if smoking causes drug resistance and whether it is WEE1 dependent. Our RNA sequencing data using WEE1 knockdown cells suggested that WEE1 inhibition and docetaxel treatment induce significantly different gene expression signatures.…”