Nicotine Induces Tumor Growth and Chemoresistance through Activation of the PI3K/Akt/mTOR Pathway in Bladder Cancer

Abstract

Continued smoking is highly associated with not only a higher incidence but also greater risk of tumor recurrence, progression, and acquired chemoresistance of urothelial carcinoma. We investigated whether nicotine affects urothelial carcinoma, and the detailed mechanism by which nicotine could induce tumor growth and any associated chemoresistance. Cell viability was evaluated in the human bladder cancer cell line T24 exposed to nicotine with or without cisplatin (CDDP) and NVP-BEZ235 as a PI3K/mTOR dual inhibitor by the WST-1 assay. Protein expression of the PI3K/Akt/mTOR pathway was investigated by Western blotting or immunohistochemical analysis. The influence of nicotine on tumor growth was also evaluated with or without CDDP and/or NVP-BEZ235 in a subcutaneous bladder tumor model. The result demonstrated that cell proliferation was increased in T24 cells after exposure to nicotine. Phospho-specific Akt (pAkt) and phospho-specific p70 S6 kinase (pS6) were significantly upregulated by nicotine exposure. Tumor growth in vivo was significantly induced by nicotine exposure in accordance with increased pS6 expression. Nicotine attenuated inhibition of T24 cell growth by CDDP and further upregulated pS6 expression in vitro and in vivo. NVP-BZE235 inhibited T24 cell proliferation and pAkt and pS6 expression induced after exposure to nicotine and/or CDDP. In conclusion, nicotine increases tumor growth and induces acquired chemoresistance through activation of the PI3K/Akt/mTOR pathway in bladder cancer.

VPS33B negatively modulated by nicotine functions as a tumor suppressor in colorectal cancer

“…Nicotine had the strongest effect on VPS33B expression at a concentration of 10 μmol/l after 96 hr. Previous reports have emphasized that nicotine promotes malignant phenotype in cervical carcinoma and bladder cancer via regulating the PI3K/AKT pathway . As shown in Figure d , nicotine suppressed the protein level of p‐PI3K, p‐AKT, c‐Jun and VPS33B in CRC cells.…”

“…Previous reports have emphasized that nicotine promotes malignant phenotype in cervical carcinoma and bladder cancer via regulating the PI3K/AKT pathway. 17,18 As shown in Figure 1d, nicotine suppressed the protein level of p-PI3K, p-AKT, c-Jun and VPS33B in CRC cells. Interestingly, we observed that c-Jun bound to the promoter of VPS33B by bioinformation software (Supporting Information Fig.…”

Identification of key pathways and genes influencing prognosis in bladder urothelial carcinoma

“…However, inhibition of p38 MAPK decreased BUC proliferation, growth, and cell invasiveness of bladder cancer via the MAPK pathway 55,56. Previous studies have demonstrated that activation of the PI3K-AKT–mechanistic target of rapamycin (mTOR) pathway promotes bladder carcinogenesis and, further, induces tumor growth and chemoresistance by nicotine 57,58. Moreover, activation of the PI3K-AKT–mTOR pathway is correlated with advanced tumor progression and unfavorable survival outcomes 59.…”

The suppressing effects of BTG3 expression on aggressive behaviors and phenotypes of colorectal cancer: Anin vitroandvivostudy

“…MDR1 and BCRP belong to efflux transporters of the ATP-binding cassette family and pumps many foreign substances out of cells [24]. Chemoresistance is induced or acquired through the activation of the PI 3 K /Akt/mTOR pathway in some malignancies [25]. Taken together, BTG3-mediated chemosensitivity was positively linked to the down-regulated expression of the chemoresistance-related genes.…”