KLHL18 inhibits the proliferation, migration, and invasion of non-small cell lung cancer by inhibiting PI3K/PD-L1 axis activity

Abstract

Background The expression of Kelch-like protein 18 (KLHL18) in non-small cell lung cancer (NSCLC) is lower than that in normal lung tissue according to the Gene Expression Profiling Interactive Analysis database. KLHL18 is a BTB domain protein and binds cullin 3 (CUL3). However, whether this complex participates in ubiquitination-mediated protein degradation in NSCLC is unclear. Therefore, we aimed to investigate the role of KLHL18 in human NSCLC cells. Results We found that KLHL18 is downregulated in cancer cells and is associated with poor prognosis. Further, its expression was significantly associated with tumor node metastasis (TNM) stage, lymph node metastasis, and tumor size. In vitro analysis of NSCLC cells showed that overexpressing KLHL18 inhibited cell proliferation, migration, and invasion. We found that the tumor-inhibitory effect of the KLHL18 protein was achieved by promoting the ubiquitination and degradation of phosphatidylinositol 3-kinase (PI3K) p85α and inhibiting the expression of PD-L1 protein, ultimately preventing tumor cell immune escape. Conclusions Our results identified the tumor-suppressive mechanism of KLHL18 and suggested that it is closely related to NSCLC occurrence and development. Further investigation of the underlying mechanism may provide new targets for NSCLC treatment.

CUL3/SPOP complex prevents immune escape and enhances chemotherapy sensitivity of ovarian cancer cells through degradation of PD-L1 protein

“… 19 More importantly, KLHL18, a BTB domain protein and binds CUL3, can suppress non-small cell lung cancer by reducing the activity of PI3K/PD-L1 axis. 37 Thus, we made a conclusion that CUL3/SPOP could degrade PD-L1 to suppress immune escape of ovarian cancer cells and promote the sensitivity of ovarian cancer cells to chemotherapy, suggestive of the critical roles of CUL3 and SPOP in ovarian cancer.…”

“…19 More importantly, KLHL18, a BTB domain protein and binds CUL3, can suppress nonsmall cell lung cancer by reducing the activity of PI3K/ PD-L1 axis. 37 Thus, we made a conclusion that CUL3/…”

Development of Clioquinol Platinum(IV) Conjugates as Autophagy-Targeted Antimetastatic Agents

“…PD-L1 as an important immune checkpoint protein could drive T-cell dysfunction and induce immunosuppression. Enhanced autophagy is related to the inhibition of PD-L1 expression in tumor cells. , Moreover, there is now a growing appreciation that the suppressed PI3K/AKT/mTOR pathway can decrease the expression of PD-L1 through promoting autophagy, thereby increasing the number of T cells and contributing to the tumor’s immunity activation. − Therefore, the PD-L1 expression was immunohistochemically stained, and the CD4 + and CD8 + tumor-infiltrating lymphocytes (TILs) in tumor tissues were detected by immunohistochemistry and immunofluorescence assays to determine the impacts of CLQ platinum­(IV) complexes on tumor immunity. Results in Figure depicted that complex 5 remarkably suppressed the secretion of PD-L1 in tumor tissues to 20.5% of the blank group, which was also obviously lower than that of platinum­(II) drugs CDDP (44.9%, P < 0.001) and OLP (55.8%, P < 0.001).…”

KLHL38 involvement in non-small cell lung cancer progression via activation of the Akt signaling pathway

“…In the present study, KLHL38 was found to promote activation of Akt and its downstream partners by promoting ubiquitin-dependent PTEN degradation. A previous study on KLHL18, another member of the KLHL family, demonstrated that the BTB domains in KLHL18 are critical for the ubiquitination of PI3Kp85α 23 . However, it was not possible here to identify which KLHL38 domains are involved in the PTEN ubiquitination process.…”