Curcumin inhibits pancreatic cancer cell proliferation by regulating Beclin1 expression and inhibiting the hypoxia-inducible factor-1α-mediated glycolytic pathway

Wencheng Guo; Yamei Ding; Chunmei Pu; Zhu Wang; Wei Deng; Xiaochao Jin

doi:10.21037/jgo-22-802

Curcumin inhibits pancreatic cancer cell proliferation by regulating Beclin1 expression and inhibiting the hypoxia-inducible factor-1α-mediated glycolytic pathway

J Gastrointest Oncol. 2022 Dec;13(6):3254-3262. doi: 10.21037/jgo-22-802.

Authors

Wencheng Guo^#¹, Yamei Ding^#², Chunmei Pu³, Zhu Wang⁴, Wei Deng⁵, Xiaochao Jin⁶

Affiliations

¹ Department of Gastroenterology, Yulin Second Hospital, Yulin, China.
² Department of Endoscopic Center, Hai'an People's Hospital, Nantong, China.
³ Department of Gastroenterology, General Hospital of Western Theater of Chinese People's Liberation Army, Chengdu, China.
⁴ Department of Traditional Chinese Medicine Oncology, Affiliated Hospital of Jiangxi Institute of Traditional Chinese Medicine, Nanchang, China.
⁵ Department of Pediatric General Internal Medicine, Gansu Provincial Maternity and Child-care Hospital, Lanzhou, China.
⁶ Department of Tumor Surgery, Chifeng Municipal Hospital, Chifeng, China.

^# Contributed equally.

Abstract

Background: Pancreatic cancer has a high degree of malignancy and high mortality. Understanding its biological status can provide more therapeutic targets for the future. The present study was to investigate whether curcumin can inhibit pancreatic cancer cell proliferation by regulating Beclin1 expression and inhibiting the hypoxia-inducible factor-1α (HIF-1α)-mediated glycolytic pathway.

Methods: Two pancreatic cancer cell lines, PANC-1 and SW1990, were treated with different concentrations of curcumin (0, 20, 40, and 60 µM). Cell viability was detected using the Cell Counting Kit-8 (CCK-8) assay and flow cytometry was performed to determine the apoptosis rate and cell cycle arrest of the pancreatic cancer cells. PANC-1 and SW1990 cells were treated with different concentrations of curcumin under hypoxic conditions for 48 hours to detect the relative expression of the Beclin1 protein. The co-immunoprecipitation (co-IP) method was used to determine whether curcumin could inhibit the interaction between Beclin1 and HIF-1α.

Results: The proliferation inhibition rates of PANC-1 cells after exposure to 0, 20, 40, and 60 µM curcumin were 0%, 31.6%, 47.2%, and 63.9%, respectively, and that of SW1990 cells were 0%, 18.8%, 46.3%, and 63.5% respectively. Western blot analyses showed decreased expression of Beclin1 in cells treated with curcumin. The expression of Beclin1 in the nucleus and cytoplasm decreased with increasing concentrations of curcumin. Co-IP results demonstrated that curcumin inhibited the interaction between Beclin1 and HIF-1α. Treatment with the higher doses of curcumin (40 and 60 µM) significantly decreased the protein expression levels of HIF-1α. In addition, the expression levels of Kidney-Specific Cadherin (HSP70, HSP90, and von Hippel-Lindau protein (pVHL) were significantly decreased in pancreatic cancer cells while the expression of prolyl hydroxylase (PHD) and receptor of activated protein kinase C (RACK1) increased significantly. Furthermore, curcumin reduced cellular adenosine triphosphate (ATP) production in a dose-dependent manner. Compared with control pancreatic cancer cells, the expression levels of GLUT1, HK2, LDHA, and PDK1 gradually decreased with increasing curcumin concentrations.

Conclusions: Curcumin can inhibit the expression of Beclin1 and HIF-1α in pancreatic cancer cells under anoxic conditions, thereby affecting the glycolysis pathway and inhibiting cell proliferation.

Keywords: Beclin1; Pancreatic cancer; curcumin; hypoxia inducible factor-1α (HIF-1α).