Knockdown of Cul4A increases chemosensitivity to gemcitabine through upregulation of TGFBI in lung cancer cells

Abstract

Abstract. Cullin 4A (Cul4A) promotes oncogenesis through overexpression and then ubiquitination-mediated proteolysis of tumor suppressors in various types of cancers. Transforming growth factor β-induced (TGFBI) has been implicated as a tumor suppressor, which enhances gemcitabine chemosensitivity in lung cancer cells. The present study aimed to investigate the association of TGFBI and Cul4A and the mechanism by which Cul4A regulates TGFBI. In addition, we also evaluated the therapeutic value of Cul4A RNAi using adenoviral transfection of Cul4A RNAi in nude mouse xenograft models. We observed that knockdown of Cul4A was associated with increased sensitivity to gemcitabine through upregulation of TGFBI in lung cancer cells. Cul4A regulated TGFBI through direct interaction and then ubiquitin-mediated protein degradation. In the nude mouse xenograft models, adenoviral transfection of Cul4A RNAi in combination with gemcitabine chemotherapy inhibited lung cancer tumor growth. As the result, combination of Cul4A RNAi with chemotherapy may provide a new approach to lung cancer treatment.

Cul4A Modulates Invasion and Metastasis of Lung Cancer through Regulation of ANXA10

“…Cells were grown in RPMI-1640 complete growth medium supplemented with 10% fetal calf serum, 10 units/mL penicillin, and 10 µg/mL streptomycin at 37 °C and 5% CO 2 . The H460 and A549 Cul4A and empty vector-transfected stable cells were generated by retroviral transduction of Cul4A shRNA as described previously in [14].…”

“…Cul4A is overexpressed in several cancers, including breast [7], mesothelioma [8], lung cancer [9], and liver cancers [10]. Cul4A also causes ubiquitination and proteolysis of p53 [11], NF2 [12], RASSF1A [13], p27 [3], TGFBI [14], and p21 [8,15] tumor suppressors through different mechanisms. Cul4A physically associates with MDM2 and it participates in the proteolysis of p53 [11].…”

“…Cul4A–DDB1 complex associates with the F-box protein Skp2 to target p27 for proteolysis [3]. Cul4A interacts with TGFBI for ubiquitination and degradation [14]. The CDK inhibitor p21 is degraded by the PCNA coupled Cul4A–DDB1 Cdt2 pathway [15].…”

“…Reduced MTSS1 expression contributes to the increased proliferation and migration of cancer cells. Depletion of cullin 1 also leads to increased expression of MTSS1 [20], while the knockdown of Cul4A is associated with the growth inhibition of lung cancer cells [14,21]. Cul4A overexpression has been observed in 50% to 87.2% of lung cancer tissues, and it has been associated with poor prognosis of lung cancer patients in previous studies [9,22].…”

miR‑21‑5p induces cell proliferation by targeting TGFBI in non‑small cell lung cancer cells

“…In USA, NSCLC was the second most prevalent cancer among all new cancer cases and cancer deaths in 2016 ( 2 ). Traditional chemotherapy regimens for NSCLC have many disadvantages such as limited efficacy, high recurrence rate, and high toxicity ( 3 ). These disadvantages limit the efficacy of drug therapy for NSCLC, so an improved understanding of the exact mechanisms of this disease and developing new, targeted therapy drugs for NSCLC is urgent.…”