Blockage of retinoic acid signaling via RARγ suppressed the proliferation of pancreatic cancer cells by arresting the cell cycle progression of the G1-S phase

Abstract

Background Ours and several studies have reported that, in some cancers, including pancreatic ductal adenocarcinoma (PDAC), the expression of squamous lineage markers, such as esophagus-tissue specific genes, correlated with a poor prognosis. However, the mechanism by which the acquisition of squamous lineage phenotypes leads to a poor prognosis remains unclear. We previously reported that retinoic acid signaling via retinoic acid receptor γ (RARγ signaling) determines the differentiation lineage into the esophageal squamous epithelium. These findings hypothesized that the activation of RARγ signaling contributed to acquiring squamous lineage phenotypes and malignant behavior in PDAC. Methods This study utilized public databases and immunostaining of surgical specimens to examine RARγ expression in PDAC. We evaluated the function of RARγ signaling by inhibitors and siRNA knockdown using PDAC cell line and patient-derived PDAC organoids. The mechanism of the tumor-suppressive effects by blockage of RARγ signaling was determined by RNA-sequencing and Western blotting. Results RARγ expression increased via transformation from normal pancreatic duct to pancreatic intraepithelial neoplasia (PanIN) and PDAC, and its expression correlated with a poor patient prognosis. In PDAC cell lines, blockage of RARγ signaling suppressed cell proliferation by inducing the cell cycle arrest in the G1 phase without causing apoptosis. We demonstrated that blockage of RARγ signaling upregulated p21 and p27 and downregulated many cell cycle genes, including cyclin-dependent kinase 2 (CDK2), CDK4 and CDK6. Furthermore, using patient-derived PDAC organoids, we confirmed the tumor-suppressive effect of RARγ inhibition and indicated the synergistic effects of RARγ inhibition with gemcitabine. Conclusions This study clarified the function of RARγ signaling in PDAC progression and demonstrated the tumor-suppressive effect of selective blockage of RARγ signaling against PDAC. These results suggested that RARγ signaling might be a new therapeutic target for PDAC.

Retinoic acid receptor regulation of decision-making for cell differentiation

“…High expression on ovarian cancer was a predictor of poor overall survival outcomes and has been linked to accelerated disease progression via the regulation of cell proliferation ( Xiu et al, 2022 ). Overexpression of RARγ in pancreatic ductal adenocarcinoma tissue and high-grade precancerous lesions was linked to a poor patient prognosis and blocking RARγ signalling supressed the proliferation of cancer cells ( Yamakowa et al, 2022 ). For the above carcinomas, a common denominator was that a high level of expression of RARγ was linked to a poor prognosis.…”

All‐trans retinoic acid exhibits anti‐proliferative and differentiating activity in Merkel cell carcinoma cells via retinoid pathway modulation

“…12 Indeed, ATRA has been administered in patients and resulted as useful in managing myelodysplastic diseases, 14,21 solid tumours 20,38 and melanoma. 22 Since ATRA is known to inhibit cancer cell proliferation by regulating cell cycle, 39 we assessed the cell cycle of MCC cells upon ATRA treatment. ATRA induced G0/G1 cell cycle arrest in MCC cells, without perturbing control cells.…”

“…Since ATRA is known to inhibit cancer cell proliferation by regulating cell cycle, 39 we assessed the cell cycle of MCC cells upon ATRA treatment. ATRA induced G0/G1 cell cycle arrest in MCC cells, without perturbing control cells.…”