Rab23 promotes the cisplatin resistance of ovarian cancer via the Shh-Gli-ABCG2 signaling pathway

Abstract

Abstract.As a novel member of the Rab GTPase family, the role of Rab23 has been reported in multiple types of tumor. However, to the best of our knowledge, the role of Rab23 in ovarian cancer (OC) has not yet been reported. In the present study, immunohistochemistry analysis demonstrated that Rab23 was upregulated in OC tissue; survival analysis indicated that Rab23 expression was associated with a reduced overall survival (OS) rate and disease-free survival (DFS) time. In vitro experiments also demonstrated the increased expression of Rab23 in the OC cells lines, A2780 and SKOV-3, compared with in the normal ovarian cell line, IOSE80. Following the silencing of ABCG2 in SKOV-3 cells, ATP-binding cassette sub-family G member 2 (ABCG2) expression was significantly downregulated both at the RNA and protein levels. The cisplatin (DDP) IC 50 declined from 43.09±7.12 µmol/l in control cells to 26.46±5.38 µmol/l in SKOV-3 cells with silenced Rab23. In contrast, in A2780 cells overexpressing Rab23 (A2780-Rab23), ABCG2 expression was significantly upregulated and the DDP IC 50 increased from 27.42±6.54 µmol/l in control cells to 45.92±5.23 µmol/l in A2780-Rab23. Investigation into the potential molecular mechanisms for this revealed that the expression of sonic hedgehog (Shh) and Gli family zinc finger 1 (Gli1) was increased in A2780-Rab23 cells, whereas silencing Rab23 in SKOV-3 cells significantly inhibited the expression of Shh and Gli1. The Gli1 inhibitor GANT-61 significantly abrogated the increased ABCG2 expression in A2780-Rab23 cells. Furthermore, the DDP IC 50 in A2780-Rab23 cells decreased significantly following the silencing of ABCG2 expression; the IC 50 declined from 51.66±8.32 µmol/l in A2780-Rab23 cells to 25.61±6.17 µmol/l in A2780-Rab23 cells with silenced ABCG2. Collectively, the results indicate that Rab23 promotes the DDP resistance of OC cells via the Shh-Gli1-ABCG2 pathway, providing the proof of principle for the further investigation of drug resistance therapy targeting Rab23.

miR-597-3p inhibits invasion and migration of thyroid carcinoma SW579 cells by targeting RAB23

“…Subsequently, RAB23 was a target to inhibit drug resistance and improve the prognosis of patients with ovarian cancer [14]. However, as far as we know, the role of miR-597-3p in thyroid carcinoma and its relationship with RAB23 has not yet been reported.…”

RAB31 Targeted by MiR-30c-2-3p Regulates the GLI1 Signaling Pathway, Affecting Gastric Cancer Cell Proliferation and Apoptosis

“…Recently, it was shown that Hh signaling via Smoothened and GLI1 requires involvement of the RAB family ( 31 ). RAB23 interacts with GLI1 to promote the progression of tumors such as breast, prostate, and ovarian cancers ( 32 – 34 ).…”

Hedgehog signaling promotes multidrug resistance by regulation of ABC transporters in oral squamous cell carcinoma

“…It has been previously shown that Hh signaling pathway is correlated with MDR in various cancers. 11,21,22 However, the relationship between Hh signaling pathway and OSCC is unclear. Thus, further investigation into the potential role of Hh signaling pathway in the MDR of OSCC is required.…”

“…5 Another report revealed the detectable interaction between SHH-GLI1-ABCG2 pathway and drug resistance in ovarian cancer. 22 As a downstream molecule of SHH signaling pathway, ABCB2 contributes to the drug resistance of pancreatic ductal adenocarcinoma cells. 28 that activation of the Hh signaling pathway upregulated expression of ABCG2 in lymphoma, which is consistent with our data.…”