Abstract
We have previously reported overexpression of antiapoptotic MCL-1 protein in human oral cancers and its association with therapy resistance and poor prognosis, implying it to be a potential therapeutic target. Hence, we investigated the efficacy and mechanism of action of Obatoclax, a BH3 mimetic pan BCL-2 inhibitor in human oral cancer cell lines. All cell lines exhibited high sensitivity to Obatoclax with complete clonogenic inhibition at 200–400 nM concentration which correlated with their MCL-1 expression. Mechanistic insights revealed that Obatoclax induced a caspase-independent cell death primarily by induction of a defective autophagy. Suppression of autophagy by ATG5 downregulation significantly blocked Obatoclax-induced cell death. Further, Obatoclax induced interaction of p62 with key components of the necrosome RIP1K and RIP3K. Necrostatin-1 mediated inhibition of RIP1K significantly protected the cells from Obatoclax induced cell death. Moreover, Obatoclax caused extensive mitochondrial stress leading to their dysfunction. Interestingly, MCL-1 downregulation alone caused mitochondrial stress, highlighting its importance for mitochondrial homeostasis. We also demonstrated in vivo efficacy of Obatoclax against oral cancer xenografts and its synergism with ionizing radiation in vitro. Our studies thus suggest that Obatoclax induces autophagy-dependent necroptosis in oral cancer cells and holds a great promise in the improved management of oral cancer patients.
Highlights
Oral squamous cell carcinoma (OSCC) is one of the most common cancers in Indian males and comprises 30– 40% of all malignancies
The present study demonstrates that Obatoclax mediates a caspase-independent, autophagy-dependent necroptosis in oral cancer cells associated with extensive mitochondrial stress
Obatoclax potently inhibits the clonogenicity of oral squamous carcinoma cells We demonstrated the efficacy of Obatoclax against four oral cancer cell lines (DOK, AW8507, AW13516, SCC029B)
Summary
Oral squamous cell carcinoma (OSCC) is one of the most common cancers in Indian males and comprises 30– 40% of all malignancies. We demonstrated predominant overexpression of antiapoptotic MCL-1 protein in oral cancer tissues versus normal and its association with therapy resistance and poor prognosis in oral cancer patients [16,17,18,19]. Apart from its canonical prosurvival function, role of MCL-1 in mitochondrial homeostasis [22], DNA damage response [23, 24] and autophagy [25] are recently emerging All these studies suggests that the antiapoptotic proteins of the BCL-2 family, MCL-1 are promising therapeutic targets in OSCC. The present study demonstrates that Obatoclax mediates a caspase-independent, autophagy-dependent necroptosis in oral cancer cells associated with extensive mitochondrial stress. We show the synergistic effect of Obatoclax with ionizing radiation treatment on oral cancer cells
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