1. Academic Validation
  2. Suppression of hypoxia-induced CAV1 autophagic degradation enhances nanoalbumin-paclitaxel transcytosis and improves therapeutic activity in pancreatic cancer

Suppression of hypoxia-induced CAV1 autophagic degradation enhances nanoalbumin-paclitaxel transcytosis and improves therapeutic activity in pancreatic cancer

  • Eur J Pharmacol. 2024 Feb 21:176431. doi: 10.1016/j.ejphar.2024.176431.
Xiangli Bai 1 Jia Xiong 2 Lin Li 3 Chao Yu 4 Chengyi Sun 5
Affiliations

Affiliations

  • 1 School of Basic Medicine, Guizhou Medical University, 5500025, Guiyang, Guizhou, China; Department of Hepatic-Biliary-Pancreatic Surgery, The Affiliated Hospital of Guizhou Medical University, 550004, Guiyang, Guizhou, China; Department of Laboratory Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430077, Wuhan, Hubei, China.
  • 2 Department of Cardiovascular Surgery, Jinan University 2nd Clinical Medicine College People's Hospital of Shenzhen, 518020, Shenzhen, Guangdong, China.
  • 3 School of Basic Medicine, Guizhou Medical University, 5500025, Guiyang, Guizhou, China; Department of Hepatic-Biliary-Pancreatic Surgery, The Affiliated Hospital of Guizhou Medical University, 550004, Guiyang, Guizhou, China.
  • 4 Department of Hepatic-Biliary-Pancreatic Surgery, The Affiliated Hospital of Guizhou Medical University, 550004, Guiyang, Guizhou, China.
  • 5 School of Basic Medicine, Guizhou Medical University, 5500025, Guiyang, Guizhou, China; Department of Hepatic-Biliary-Pancreatic Surgery, The Affiliated Hospital of Guizhou Medical University, 550004, Guiyang, Guizhou, China. Electronic address: sunchengyi2014@163.com.
Abstract

Nanoalbumin-paclitaxel (nab-paclitaxel) is a standard chemotherapy for pancreatic Cancer but has shown limited efficacy. However, the mechanism through which circulating nab-paclitaxel passes through the tumour vascular endothelium has not been determined. In our study, a new nonradioactive and highly sensitive method for analysing nab-paclitaxel transcytosis was established. Based on these methods, we found that hypoxia significantly enhanced the autophagic degradation of CAV1 and therefore attenuated caveolae-mediated nab-paclitaxel transcytosis across endothelial cells (ECs). In a proof-of-concept experiment, higher levels of CAV1, accompanied by lower levels of LC3B, were observed in the vascular endothelium of pancreatic Cancer tissues collected from patients who showed a good response to nab-paclitaxel compared with those from patients who showed a poor response to nab-paclitaxel. Furthermore, both in vivo and in vitro studies confirmed that suppressing the autophagic degradation of CAV1 via EC-specific ATG5 knockdown or hydroxychloroquine sulfate (HCQ) treatment significantly enhanced nab-paclitaxel translocation across the endothelial barrier into pancreatic Cancer cells and amplified the inhibitory effect of nab-paclitaxel on pancreatic tumour growth. The stimulation of CAV1 expression by EC-specific overexpression of exogenous CAV1 or administration of gemcitabine hydrochloride (GE) had the same effect. These results demonstrated that suppressing CAV1 autophagic degradation is a novel translatable strategy for enhancing nab-paclitaxel chemotherapeutic activity in the treatment of pancreatic Cancer.

Keywords

Autophagy; CAV1; Endothelial cells; Nanoalbumin-paclitaxel transcytosis; Pancreatic cancer.

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