HE4 overexpression decreases pancreatic cancer Capan-1 cell sensitivity to paclitaxel via cell cycle regulation

Abstract

Background: Paclitaxel is a first-line chemotherapy drug for pancreatic, ovarian, endometrial cancers and other malignancies. However, its efficacy is often compromised by decreased cell sensitivity or the development of resistance. Human epididymis protein 4 (HE4) is highly expressed in gynecologic and pancreatic cancer tissues, and its serum levels are used for patient triage and assistant diagnosis of gynecologic cancers. Previous studies have shown that HE4 overexpression could promote cancer cell proliferation and the growth of tumor xenografts, which suggests its potential involvement in cancer chemosensitivity. Methods: Two pancreatic cancer cell lines, Capan-1 and Suit-2, were transiently transfected with an HE4 overexpression plasmid, and transfected cells were treated with paclitaxel. S-phase cells were labeled using BrdU, and cell positivity rates were determined by counting BrdU-positive cells. Following HE4 overexpression and/or drug treatment, a western blotting analysis was performed to determine the protein alterations of PCNA and p21, two important cell cycle regulators. Results: HE4 overexpression not only promoted the proliferation of the Capan-1 pancreatic cells, but also significantly decreased cell sensitivity to paclitaxel. Results from western blotting showed that paclitaxel inhibited cell proliferation by decreasing the expression of PCNA and increasing the expression of p21. Data analysis indicated interactive actions between HE4 function and paclitaxel effects, both converging to cell cycle regulation. Conclusion: These findings suggest that HE4 could be a potential therapeutic target for the sensitization of pancreatic cancer cells to paclitaxel treatment. HE4 expression levels may be used to predict the sensitivity of pancreatic cancer patients to paclitaxel.

Predictive Value of HE4 in Platinum-Based Chemotherapy for Ovarian Cancer: A Systematic Review

“…Li et al (30) reported that HE4 overexpression in endometrial cancer cells promoted cell proliferation, stromal infiltration, and other malignant behaviors of cancer cells. HE4 overexpression promotes the proliferation of CAPAN-1 pancreatic cells and significantly reduces the cells' paclitaxel sensitivity (31). Ribeiro et al (32) indicated that overexpression of HE4 resulted in increased resistance of the SKOV3 and OVCAR8 OC cell lines to cisplatin and paclitaxel, and that HE4 knockout could partially reverse resistance.…”

“…( 30 ) reported that HE4 overexpression in endometrial cancer cells promoted cell proliferation, stromal infiltration, and other malignant behaviors of cancer cells. HE4 overexpression promotes the proliferation of CAPAN-1 pancreatic cells and significantly reduces the cells’ paclitaxel sensitivity ( 31 ). Ribeiro et al.…”

Potential Role of Exosomes in the Chemoresistance to Gemcitabine and Nab-Paclitaxel in Pancreatic Cancer

“…Another gene that seems to have a specific role in the chemoresistance of PDAC is human epididymis protein 4 that causes both cancer cell growth and reduced sensitivity to paclitaxel in PDAC cell lines. These results suggest that HE4 expression levels may be used to predict the sensitivity of PDAC patients to paclitaxel [ 39 ].…”

Clinical Significance And Potential Mechanisms of The RNA Methyltransferase KIAA1429 In Osteosarcoma

“…For example, the lncRNA PITPNA-AS1/miR-876-5p/c-MET axis regulates the cell cycle, and promotes the progression of cervical cancer [23]. Additionally, HE4 overexpression reduces the sensitivity of pancreatic cancer to paclitaxel by deregulating the cell cycle pathway [24]. Glycyrrhizic acid represses the proliferation of gastric cancer cells by inhibiting the cell cycle [25].…”