Caveolin-1 regulates Mcl-1 stability and anoikis in lung carcinoma cells

Abstract

Both caveolin-1 (Cav-1) and Mcl-1 have been implicated in the regulation of cancer cell anoikis, but their relationship and underlying mechanisms of regulation are not known. The present study demonstrated for the first time that Cav-1 regulates Mcl-1 through protein-protein interaction and inhibits its downregulation during cell anoikis in human lung cancer cells. Immunoprecipitation and immunocytochemistry studies showed that Cav-1 interacted with Mcl-1 and prevented it from degradation via the ubiquitin-proteasome pathway. Mcl-1 and Mcl-1-Cav-1 complex were highly elevated in Cav-1-overexpressing cells but were greatly reduced in Cav-1 knockdown cells. Consistent with this finding, we found that Mcl-1 ubiquitination was significantly attenuated by Cav-1 overexpression but increased by Cav-1 knockdown. Together, our results indicate a novel role of Cav-1 in anoikis regulation through Mcl-1 interaction and stabilization, which provides a new insight to the pathogenesis of metastatic lung cancer and its potential treatment.

Nitric oxide induces cancer stem cell-like phenotypes in human lung cancer cells

“…Several lines of evidence have pointed out that Cav-1 may contribute to the aggressiveness and chemoresistance of human cancer cells, including lung carcinoma, ovarian carcinoma, colon adenocarcinoma, and breast adenocarcinoma cells (31,37,38). Cav-1 expression has been linked to increased cell motility and anoikis resistance (11,12,27,28,30,42,45,59), two important features of metastatic cancer cells. In this study, we provide new evidence that NO increases the motility and resistance to anoikis of human lung cancer cells through a Cav-1-dependent mechanism.…”

“…Furthermore, Cav-1 can interact with Mcl-1 and improve its stability, leading to anoikis resistance of lung cancer cells (12).…”

“…Cav-1 is a scaffolding protein found in the cellular structure caveolae, which has been shown by our group and others to regulate the aggressiveness of cancer cells by increasing their motility and resistance to anoikis (11,27,28,30,42,45,59). It has also been shown to increase cell survival under nonadherent conditions via Mcl-1 stabilization (12) and upregulation of activated protein kinase B (Akt) (6). In this study, we used molecular and pharmacological approaches to investigate the role of NO in Cav-1 and CSC regulation and their impact on the invasive and anoikis properties of human lung cancer cells.…”

Potential Anti-metastasis Natural Compounds for Lung Cancer

“…In mechanistic detail, CAV-1 was shown to inhibit anoikis in lung cancer cells by its binding on and stabilizing of anti-apoptotic MCL-1 protein (25). The direct interaction of CAV-1 protects MCL-1 from ubiquitinproteasomal degradation (25).…”

“…In mechanistic detail, CAV-1 was shown to inhibit anoikis in lung cancer cells by its binding on and stabilizing of anti-apoptotic MCL-1 protein (25). The direct interaction of CAV-1 protects MCL-1 from ubiquitinproteasomal degradation (25). Other possible mechanism of CAV-1 on anoikis resistance is that the protein can upregulate the insulin-like growth factor-I receptors and enhance its downstream AKT signaling (26).…”