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Keywords

autophagy, chemoresistance, nicotine, PKM2, paclitaxel

Abstract

Persistent smoking is associated with poorer clinical outcomes in bladder cancer, possibly because nicotine promotes cancer cell proliferation and chemoresistance via activation of STAT3 and ERK1/2 signaling. Pyruvate kinase M2 (PKM2) is a central regulator of metabolic reprogramming that supports glycolysis and mitochondrial remodeling, thereby maintaining energy homeostasis, redox balance, and resistance to apoptosis. Given the close interplay between autophagy and apoptotic pathways, this study investigated PKM2-driven glycolysis and its coordination with mitochondrial function and autophagic regulation. T24 bladder cancer cells were used to investigate nicotine-induced paclitaxel resistance by assessing cell viability, alterations in energy metabolism, autophagy induction, and apoptosis. In addition, molecular changes were characterized using next-generation sequencing (NGS). We proved that nicotine may act as a stressor or growth factor to induce PKM2 expression, thereby altering cellular metabolism, glycolysis, proliferation, and autophagy, while also enhancing cancer cell resistance to anticancer drugs. Prolonged nicotine treatment activated Stat3-PKM2 signaling in T24 cells, leading to enhanced mitochondrial energy metabolism and glycolytic flux. This increased ATP availability supported cell survival under chemotherapeutic stress by inducing autophagy and attenuating apoptotic signaling. These findings highlight the role of PKM2 in mediating chemotherapy resistance and emphasize the need to evaluate the carcinogenic potential and mechanisms of environmental toxicants.

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Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

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