Drp1-mediated mitochondrial fission contributes to baicalein-induced apoptosis and autophagy in lung cancer via activation of AMPK signaling pathway

Abstract

Baicalein (BA), a natural compound extracted from Scutellaria baicalensis Georgi, has been reported to exert antitumor effect in various cancers. However, the underlying mechanisms have not been well demonstrated. In the present study, we focused on the relationship between mitochondrial fission and BA-induced apoptosis and autophagy. We showed that BA inhibited cell viability and induced mitochondrial apoptosis in A549 and H1299 lung cancer cells. BA induced the loss of mitochondrial membrane potential (MMP) and the release of cytochrome c and apoptosis inducing factor (Aif) from mitochondria to cytoplasm. Meanwhile, BA induced autophagy and activated autophagic flux. Furthermore, we found that BA induced mitochondrial fission and mitochondrial impairment. Blocking mitochondrial fission by mdivi-1 attenuated BA-induced apoptosis and autophagy. Moreover, BA activated AMP-activated protein kinase (AMPK) pathway. Knockdown of AMPK with lentivirus encoded AMPKα also attenuated BA-induced mitochondrial fission, apoptosis and autophagy. Our in vivo data confirmed that BA inhibited tumor growth and induced apoptosis and autophagy in a Lewis lung carcinoma (LLC) xenograft model via activation of AMPK/mitochondrial fission pathway. Our study highlights the critical role of AMPK/mitochondrial fission pathway in the regulation of BA-induced apoptosis and autophagy. These results revealed the molecular mechanism of the anti-lung cancer property of BA and provided novel perspectives for the application of BA in the treatment of lung cancer.

Deubiquitinase USP35 modulates ferroptosis in lung cancer via targeting ferroportin

“…To inhibit necrosis, apoptosis, autophagy, mitophagy, and ferroptosis, the cells were treated with Nec-1 (10 µmol/L), Z-VAD (10 µmol/L), CQ (25 µmol/L), Mdivi-1 (15 µmol/L), CsA (5 µmol/L), Fer-1 (1 µmol/L) or Lip-1 (0.2 µmol/L) for 96 h after the removal of lentiviral vectors. [29][30][31] To neutralize the excessive iron or ROS, membrane permeable (CPX, 5 µmol/L) and impermeable (DFO, 100 µmol/L) iron chelators and GSH (1 mmol/L) were used. 30,32,33 Besides, the cells were incubated with erastin (5 µmol/L) or RSL3 (2 µmol/L) for 96 h after the removal of lentiviral vectors.…”

Autophagy: Mechanisms and Therapeutic Potential of Flavonoids in Cancer

“…Baicalein also reversed drug resistance by inhibiting autophagy [ 49 ]. The overexpressed mTOR gene in malignant liver tumors upregulates CD133 and promotes the cytochemical resistance, which means that clinical trials show a poor prognosis.…”

“…After the treatment of BEL-7402/5-FU cells with baicalein, the multidrug resistance could be reversed by baicalein through inducing autophagy in a concentration-dependent manner. The mechanism may be related to the downregulation of P-gp and Bcl-xl expression [ 49 ]. The receptor for advanced glycation end products (RAGE) is highly expressed in diverse tumor cells, acting on the inflammatory pathway to promote the development of tumors.…”

Anti-Lung Cancer Targets of Radix Paeoniae Rubra and Biological Molecular Mechanism: Network Pharmacological Analyses and Experimental Validation

“…A total of 5*10 6 A549 cells suspended in 100ul PBS were subcutaneously injected into the right flank of anesthetized BALB/c nude mice to establish the subcutaneous xenograft model. When the tumor volume was about 80 mm 3 , these mice were divided randomly into three groups: the control group (0.5% CMS-Na, N=6), high dose BAI group (dissolved in 0.5% CMC-Na, BAI-H, 100 mg/kg, N=6), low dose BAI group (dissolved in 0.5% CMC-Na, BAI-L, 50 mg/kg, N=6), 25 , 26 and given intragastric administration of 0.2 mL 5 days a week. After 2 weeks, the mice were anesthetized by 1% pentobarbital sodium and sacrificed by decapitation.…”

“…Apoptosis was demonstrated and quantified by flow cytometry analysis using FITC Annexin V Apoptosis Detection Kit I (BD, America). 3 , these mice were divided randomly into three groups: the control group (0.5% CMS-Na, N=6), high dose BAI group (dissolved in 0.5% CMC-Na, BAI-H, 100 mg/kg, N=6), low dose BAI group (dissolved in 0.5% CMC-Na, BAI-L, 50 mg/kg, N=6), 25,26 and given intragastric administration of 0.2 mL 5 days a week. After 2 weeks, the mice were anesthetized by 1% pentobarbital sodium and sacrificed by decapitation.…”