Calcium calmodulin dependent kinase kinase 2 - a novel therapeutic target for gastric adenocarcinoma

Subbannayya, Yashwanth; Syed, Nazia; Barbhuiya, Mustafa A.; Raja, Remya; Marimuthu, Arivusudar; Sahasrabuddhe, Nandini A.; Pinto, Sneha M.; Manda, Srikanth S.; Renuse, Santosh; Manju, H. C.; Zameer, Mohammed; Sharma, Jyoti; Brait, Mariana; Srikumar, Kotteazeth; Roa, Juan Carlos; Kumar, Manish; Kumar, KV Veerendra; Prasad, T. S. Keshava; Ramaswamy, Girija; Kumar, Rekha V.; Pandey, Akhilesh; Gowda, Harsha; Chatterjee, Aditi

doi:10.4161/15384047.2014.972264

Cited by 61 publications

(80 citation statements)

References 55 publications

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“…Second, the other major AMPKK, CAMKKβ is not a TS gene in human cancer [136–138]. In fact, CAMKKβ is overexpressed up to 7-fold in 92/98 (94%) of gastric cancer [141], and played an AMPK-mediated role in metabolic reprograming, migration and invasion in prostate and colon cancer [126,128,142,143]. It is reasonable to predict that oncogene-induced ER stress and calcium disequilibrium can activate a specific pool of the AMPK heterotrimer through CAMKKβ.…”

Section: The Many Functions Of Ampkmentioning

confidence: 99%

Evolving Lessons on the Complex Role of AMPK in Normal Physiology and Cancer

Dasgupta

Chhipa

2016

Trends in Pharmacological Sciences

110

120

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AMP kinase (AMPK) is an evolutionarily conserved enzyme required for adaptive responses to various physiological and pathological conditions. AMPK executes numerous cellular functions, some of which are often perceived at odds with each other. While AMPK is essential for embryonic growth and development, its full impact in adult tissues is revealed under stressful situations that organisms face in the real world. Conflicting reports about its cellular functions, particularly in cancer, are intriguing and a growing number of AMPK activators are being developed to treat human diseases such as cancer and diabetes. Whether these drugs will have only context-specific benefits or detrimental effects in the treatment of human cancer will be a subject of intense research. Here we review the current state of AMPK research with an emphasis on cancer and discuss the yet unresolved context-dependent functions of AMPK in human cancer.

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Section: The Many Functions Of Ampkmentioning

confidence: 99%

Evolving Lessons on the Complex Role of AMPK in Normal Physiology and Cancer

Dasgupta

Chhipa

2016

Trends in Pharmacological Sciences

110

120

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“…52 Briefly, the cells were seeded at a density of 3£10 3 , transfected with either SRPK2 siRNA or a scrambled siRNA as a control. The cells were allowed to grow for 10-12 days and the colonies were fixed with methanol, stained with 4% methylene blue and counted.…”

Section: Colony Formation Assaysmentioning

confidence: 99%

“…52 Briefly, the invasive ability of the cells was assayed using polyethylene terephthalate (PET) membrane (8-mm pore size) (Catalog # 353097, BD Biosciences). The upper compartment of the culture insert was coated with Matrigel (Catalog # 354234, BD Biosciences).…”

Section: Cell Invasion Assaysmentioning

confidence: 99%

Dysregulation of splicing proteins in head and neck squamous cell carcinoma

Radhakrishnan

Nanjappa

Raja

et al. 2016

Cancer Biology & Therapy

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ABSRTRACTSignaling plays an important role in regulating all cellular pathways. Altered signaling is one of the hallmarks of cancers. Phosphoproteomics enables interrogation of kinase mediated signaling pathways in biological systems. In cancers, this approach can be utilized to identify aberrantly activated pathways that potentially drive proliferation and tumorigenesis. To identify signaling alterations in head and neck squamous cell carcinoma (HNSCC), we carried out proteomic and phosphoproteomic analysis of HNSCC cell lines using a combination of tandem mass tag (TMT) labeling approach and titanium dioxide-based enrichment. We identified 4,920 phosphosites corresponding to 2,212 proteins in six HNSCC cell lines compared to a normal oral cell line. Our data indicated significant enrichment of proteins associated with splicing. We observed hyperphosphorylation of SRSF protein kinase 2 (SRPK2) and its downstream substrates in HNSCC cell lines. SRPK2 is a splicing kinase, known to phosphorylate serine/arginine (SR) rich domain proteins and regulate splicing process in eukaryotes. Although genome-wide studies have reported the contribution of alternative splicing events of several genes in the progression of cancer, the involvement of splicing kinases in HNSCC is not known. In this study, we studied the role of SRPK2 in HNSCC. Inhibition of SRPK2 resulted in significant decrease in colony forming and invasive ability in a panel of HNSCC cell lines. Our results indicate that phosphorylation of SRPK2 plays a crucial role in the regulation of splicing process in HNSCC and that splicing kinases can be developed as a new class of therapeutic target in HNSCC.

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“…13,16,17 Previous study from our group demonstrated that silencing or inhibiting CaMKK2 activity inhibited cellular proliferation, colony formation and invasive ability of gastric cancer cells. 15 In this study, we determined the role of CaMKK2 as an alternative to curcumin in HNSCC.…”

Section: Introductionmentioning

confidence: 99%

“…CaMKK2 has been reported to be elevated in gastric, prostate and hepatic cancers. [13][14][15] CaMKK2 has been shown to regulate growth, migration and progression of prostate cancer cells. 13,16,17 Previous study from our group demonstrated that silencing or inhibiting CaMKK2 activity inhibited cellular proliferation, colony formation and invasive ability of gastric cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Investigation of curcumin-mediated signalling pathways in head and neck squamous cell carcinoma

Nanjappa

Sathe

Jain

et al. 2017

Translational Research in Oral Oncology

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Objectives: Curcumin has been shown to exhibit anti-neoplastic effects. However, due to its poor bioavailability, the use of curcumin as an anti-cancer drug is limited. Thus, it is necessary to identify molecules as an alternative to curcumin that could serve as anti-cancer targets. In this study, we attempted to understand the underlying curcumin-mediated signalling pathways contributing to anti-neoplastic effects of curcumin. Methods: We carried out mass spectrometry-based phosphoproteomic analysis of head and neck cancer cell line, CAL 27, treated with and without curcumin to identify curcumin-mediated signalling pathways. Serine/threonine kinases were enriched using titanium dioxide.Results: This resulted in the identification of 5921 phosphopeptides corresponding to 1878 proteins. Of these, 275 and 183 phosphopeptides corresponding to 335 and 242 proteins (!2.0-fold) were found to be hyper-and hypo-phosphorylated, respectively, in response to curcumin treatment. Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), a serine/ threonine kinase, and its downstream target protein kinase AMP-activated non-catalytic subunit beta 1 (PRKAB1) were found to be hypo-phosphorylated when treated with curcumin. Further, silencing or inhibiting CaMKK2 resulted in decreased invasion and colony forming ability of not only CAL 27 cells but also other head and neck squamous cell carcinoma (HNSCC) cell lines. Further, Western blot analysis showed that curcumin-mediated signalling is corroborated by CaMKK2. Conclusions: Taken together, our results suggest that CaMKK2 could be a novel therapeutic target in HNSCC and can serve as an alternative to curcumin.

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Calcium calmodulin dependent kinase kinase 2 - a novel therapeutic target for gastric adenocarcinoma

Cited by 61 publications

References 55 publications

Evolving Lessons on the Complex Role of AMPK in Normal Physiology and Cancer

Evolving Lessons on the Complex Role of AMPK in Normal Physiology and Cancer

Dysregulation of splicing proteins in head and neck squamous cell carcinoma

Investigation of curcumin-mediated signalling pathways in head and neck squamous cell carcinoma

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