Targeting MCL-1 sensitizes human esophageal squamous cell carcinoma cells to cisplatin-induced apoptosis

Abstract

BackgroundEsophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies in China and is an exceptionally drug-resistant tumor with a 5-year survival rate less than 15%. Cisplatin is the most commonly used conventional chemotherapeutic drug for the treatment of ESCC, but some patients have a poor response to cisplatin-based chemotherapy. New strategies that could enhance chemosensitivity to cisplatin are needed.MethodsWe used reverse transcription-RCR (RT-PCR), immunoblot, immunohistochemical (IHC) staining, anchorage-dependent and -independent growth assays, co-immunoprecipitation (Co-IP) assay, RNA interference and in vivo tumor growth assay to study the expression of MCL-1 in ESCCs and the response of ESCC cells to cisplatin.ResultsThe present study showed that MCL-1 expression was significantly increased in ESCC tissues compared to normal adjacent tissues and was associated with depth of invasion and lymph node metastasis. Knockdown of MCL-1 produced significant chemosensitization to cisplatin in association with caspase-3 activation and PARP cleavage in KYSE150 and KYSE510 cells. The selective MCL-1 inhibitor UMI-77 caused dissociation of MCL-1 from the proapoptotic protein BAX and BAK, and enhanced KYSE150 and KYSE510 cells to cisplatin-induced apoptosis accompanied by caspase-3 activation and PARP cleavage.ConclusionsThe current study suggests that MCL-1 contributes to the development of ESCC and is a promising therapeutic target for chemosensitization of ESCC cells to cisplatin. This might provide a scientific basis for developing effective approaches to treat the subset of ESCCs patients with MCL-1 overexpression.

Promotion of ubiquitination-dependent survivin destruction contributes to xanthohumol-mediated tumor suppression and overcomes radioresistance in human oral squamous cell carcinoma

“…Anchorage-independent cell growth. The anchorage-independent cell growth assay was performed as described previously (18). Briefly, the Eagle's basal medium containing 10% FBS, 0.6% agar, and different concentration of xanthohumol was loading to a six-well plate as an agar base.…”

Isoliquiritigenin Suppressed Esophageal Squamous Carcinoma Growth by Blocking EGFR Activation and Inducing Cell Cycle Arrest

“…e soft agar assay was performed as described previously [27]. Briefly, 3 ml basal medium Eagle's medium containing 0.6% agar, 10% FBS, and various concentrations of ILQ was loaded into a 6-well plate.…”

Overexpression of Myocardin-related transcription factor-A attenuated middle cerebral artery occlusion/reperfusion-induced apoptosis via the Mcl-1/Cyt C/cleaved caspase 3 pathway

“…Studies have shown that Mcl-1 has anti-apoptotic actions by binding and sequestering pro-apoptotic proteins Bak and Bax to inhibit the initiation of the mitochondrial apoptotic pathway. 39,40 Mitochondrial apoptosis, also referred to as the intrinsic pathway, plays an irreplaceable role in I/R injury. After cerebral ischemia, the outer membrane of the mitochondria becomes permeable, and Cyt C is released from the mitochondria intermembrane space to the cytoplasm, thereby binding to the Apaf-1 and forming the apoptosome, which in turn activates caspase-3, eventually leading to irreversible apoptosis.…”