Ubenimex Combined with Pemetrexed Upregulates SOCS1 to Inhibit Lung Adenocarcinoma Progression via the JAK2-STAT3 Signaling Pathway

Abstract

To study the effects of ubenimex (UBE) combined with pemetrexed (PEM) on lung adenocarcinoma cell behavior and its molecular mechanism, the tissue samples from lung adenocarcinoma patients who received PEM chemotherapy, those with PEM combined with UBE chemotherapy, and healthy volunteers were retrieved and analyzed. The expression levels of the suppressor of cytokine signaling 1 (SOCS1) in the human lung adenocarcinoma cancer cell lines A549 and PC-9 and tissues were detected by qRT-PCR. MTT assay was performed for cell proliferation. Cell apoptosis was detected by flow cytometry. Cell invasion ability was assessed using the Transwell assay. The expression levels of the JAK2/STAT3 signaling pathway proteins and apoptosis-related proteins were detected by Western blot. The antitumor effect of PEM combined with UBE was tested in nude mice using the tumor formation assay. Our results showed that UBE treatment, alone or combined with PEM, inhibited lung adenocarcinoma cell migration, invasion, and proliferation; promoted apoptosis; significantly increased the G0/G1-phase cell ratio; reduced the S-phase cell ratio; and inhibited the in vivo growth of tumor cells. UBE alone or in combination with PEM also inhibited the JAK2/STAT3 signaling pathway in lung adenocarcinoma cells. In addition, UBE combined with PEM therapy was associated with increased SOCS1 expression in patients’ serum and knocking down SOCS1 reversed the antitumor effects of UBE and PEM. Overall, combination therapy with UBE and PEM could inhibit the JAK2-STAT3 signaling pathway by upregulating SOCS1 expression to hinder the progression of lung adenocarcinoma cells.

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“…Khan et al found that the deficiency of SOCS1 increases susceptibility to hepatocellular carcinoma (HCC), thereby reinforcing cell adaptation to oxidative stress and fostering tumor growth . Chen et al demonstrated that the combination of Ubenimex and Pemetrexed could inhibit the JAK2-STAT3 signaling pathway by upregulating SOCS1 expression, thus impeding the development of cancer cells . The SYVN1 gene encodes E3 ligase synovium protein 1 (SYVN1), which involves the development and metastasis of hepatocellular carcinoma.…”

“…54 Chen et al demonstrated that the combination of Ubenimex and Pemetrexed could inhibit the JAK2-STAT3 signaling pathway by upregulating SOCS1 expression, thus impeding the development of cancer cells. 55 The SYVN1 gene encodes E3 ligase synovium protein 1 (SYVN1), which involves the development and metastasis of hepatocellular carcinoma. After knocking down SYVN1, the migration and invasion ability of liver cancer cells were decreased.…”