Activation of oncogenic signaling kinase PAK1 by ionising radiation confers an aggressive phenotype in head and neck squamous cell carcinoma.

Head and neck squamous cancers are very aggressive tumors often diagnosed in late stages with poor prognosis. HNSCCs are usually treated by a course of radiation (IR) therapy and followed by surgery. These treatment regimens fail to bring a complete response. Molecular signatures in tumors are attributed to this response and an improved understanding of the signaling events could offer new avenues for therapy. Here, we show that P21 activated kinase-1 (PAK1) - an oncogenic signaling serine/threonine kinase, is activated upon exposure to IR and this leads to an accelerated tumorigenic character in HNSCC cells. Our results show that PAK1 is highly expressed in HNSCC cell lines, as compared to normal buccal mucosa cells and when HNSCC cells were exposed to IR, they show activated PAK1 and an aggressive phenotype as determined by in vitro functional assays. PAK1 levels were elevated in HNSCC as compared to adjacent normal oral tissues and our results also show convincing evidence of activated PAK1 in patient tumor samples of post- IR treatment as compared to pre-IR treatment and is associated with poor survival. Pak1 Knockout (KO) clones in HNSCC cells showed that they were more sensitive to IR as compared to wild type (wt) cells. This altered sensitivity to IR was attributed to enhanced DNA damage response modulated by PAK1 in cells. Overall, our results suggest that PAK1 expression in HNSCC could be a critical determinant in IR therapy response and silencing PAK1 is likely to be a treatment modality to improve clinical outcomes.

p21 activated kinase-1 and tamoxifen - A deadly nexus impacting breast cancer outcomes.

Tamoxifen is a commonly used drug in the treatment of ER + ve breast cancers since 1970. However, development of resistance towards tamoxifen limits its remarkable clinical success. In this review, we have attempted to provide a brief overview of multiple mechanism that may lead to tamoxifen resistance, with a special emphasis on the roles played by the oncogenic kinase- PAK1. Analysing the genomic data sets available in the cBioPortal, we found that PAK1 gene amplification significantly affects the Relapse Free Survival of the ER + ve breast cancer patients. While PAK1 is known to promote tamoxifen resistance by phosphorylating ERα at Ser305, existing literature suggests that PAK1 can fuel up tamoxifen resistance obliquely by phosphorylating other substrates. We have summarised some of the approaches in the mass spectrometry based proteomics, which would enable us to study the tamoxifen resistance specific phosphoproteomic landscape of PAK1. We also propose that elucidating the multiple mechanisms by which PAK1 promotes tamoxifen resistance might help us discover druggable targets and biomarkers.

Antioxidant Antagonises Chemotherapeutic Drug Effect in Lung Cancer Cell Line A549.

OBJECTIVE: This study aimed to find whether antioxidants increase or decrease the effect of chemotherapeutic drug in the in vitro model. METHODS: Small lung Cancer cell line (A549) was treated with anticancer drug 6-Thioguanine (6-TG) at different concentration viz., 1, 10, 50 and 100µM and the proliferation was measured using MTT assay. The antioxidant N-Acetyl Cysteine (NAC) in different ratios viz., 1mM, 5mM and 10mM were assayed for their effect in proliferation on the A549 cells alone and in combination with 6-TG. RESULTS: Our experiment proves that anticancer drug 6-TG decreases the proliferation and the antioxidant NAC enhances the proliferation of A549 cells. Strikingly when co-treated with 6-TG, the antioxidant NAC diminished the proliferation reduction action of 6-TG on A549 cells. CONCLUSION: Our results suggest that antioxidants in fact benefit the tumor cell growth when treated alone and when in combination with anticancer drug, it severely impair the activity of the drug. We propose that extreme care should be taken when prescribing antioxidants alone or in combination with chemotherapeutics.