Protein phosphatase 2A-B56γ-Drp1-Rab7 signaling axis regulates mitochondria-lysosome crosstalk to sensitize the anti-cancer therapy of hepatocellular carcinoma.

Mitochondria-lysosome crosstalk is an intercellular communication platform regulating mitochondrial quality control (MQC). Activated dynamin-related protein 1 (Drp1) with phosphorylation at serine 616 (p-Drp1Ser616) plays a critical role in mitophagy-dependent cell survival and anti-cancer therapy for hepatocellular carcinoma (HCC). However, the underlying mechanisms that p-Drp1Ser616 involved in regulating mitochondria-lysosome crosstalk and mediating anti-HCC therapy remain unknown. HCC cells and mouse xenograft models were conducted to evaluate the relationship between p-Drp1Ser616 and Ras-associated protein 7 (Rab7) and the underlying mechanism by protein phosphatase 2A (PP2A)-B56γ regulating mitophagy via dephosphorylation of p-Drp1Ser616 in HCC. Herein, we found that Drp1 was frequently upregulated and was associated with poor prognosis in HCC. Mitochondrial p-Drp1Ser616 was a novel inter-organelle tethering protein localized to mitochondrion and lysosome membrane contact sites (MCSs) via interaction with Rab7 to trigger an increase in the mitochondria-lysosome crosstalk, resulting in PINK1-Parkin-dependent mitophagy and anti-apoptosis in HCC cells under the treatment of chemotherapy drugs. Moreover, we demonstrate that B56γ-mediated direct dephosphorylation of p-Drp1Ser616 inhibited mitophagy and thus increased mitochondria-dependent apoptosis. Overall, our findings demonstrated that activation of B56γ sensitizes the anti-cancer effect of HCC chemoprevention via dephosphorylated regulation of p-Drp1Ser616 in inhibiting the interaction between p-Drp1Ser616 and Rab7, which may provide a novel mechanism underlying the theranostics for targeting intervention in HCC.

Impact of weight gain following smoking cessation on one-year outcome after drug-eluting stent implantation / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Weight gain following smoking cessation increases cardiovascular risk, but its effects on prognosis after percutaneous coronary intervention (PCI) remain unclear. This study aimed to investigate the relationship between weight gain post smoking cessation and one-year clinical outcome in patients who underwent PCI with drug-eluting stent (DES).</p><p><b>METHODS</b>A total of 895 consecutive male smoking patients were divided into quitters (n = 437) and continuers (n = 458) according to their smoking status after PCI. Weight gain, major adverse cardiac events (MACE, including cardiac deaths, myocardial infarction and revascularization), and recurrent angina were recorded during follow-up for one year.</p><p><b>RESULTS</b>Average weight gain in quitters was more than that in continuers (1.5 kg vs. -0.03 kg, P < 0.001). Weight was unchanged or increased by more than 1.5 kg in 78.17% of continuers, while 50.57% of quitters had a weight gain of less than 1.5 kg. Compared with continuers, MACE in quitters was significantly reduced after PCI (6.12% vs. 4.81%, P = 0.049), especially recurrent angina (13.97% in continuers vs. 9.84% in quitters, P = 0.027). After adjusting for weight gain and other factors, smoking cessation was independently associated with a lower risk of MACE and recurrent angina (OR = 0.73, P = 0.035). However, weight gain > 1.5 kg (OR = 1.55, P = 0.026) could curtail the benefits from smoking cessation.</p><p><b>CONCLUSIONS</b>Weight gain may reduce the benefits of smoking cessation after PCI with DES implantation. Thus, although smoking cessation is recommended after PCI, weight control should also be highly encouraged for these patients.</p>