Calpain and oral cancer – A novel approach to detect cancer cell invasion

Sayani Shome; Shiladitya Sil

doi:10.4103/ijds.ijds_77_21

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Year : 2022 | Volume : 14 | Issue : 1 | Page : 51-52

Calpain and oral cancer – A novel approach to detect cancer cell invasion

Sayani Shome¹, Shiladitya Sil²
¹ Department of Oral and Maxillofacial Pathology, Haldia Institute of Dental Sciences and Research, Haldia, West Bengal, India
² Department of Dentistry, Burdwan Medical College and Hospital, Burdwan, West Bengal, India

Date of Submission	16-Jun-2021
Date of Acceptance	01-Jul-2021
Date of Web Publication	31-Dec-2021

Correspondence Address:
Sayani Shome
19/U 6, Gitabitan Apartment, Dumdum Road, Kolkata - 700 030, West Bengal
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/ijds.ijds_77_21

Abstract

Calpain is a Ca²⁺ dependent non-lysosomal cytosolic and mitochondrial cysteine protease found in tissue and organ specific manner in human being and in other mammals. It is observed to be an initiator for cancer cell propagation and invasion in Oral Squamous Cell Carcinoma (OSCC) and also a regulator of apoptosis. A concised review on this novice molecule is re-explored based on previous and ongoing studies in the following article.

Keywords: Apoptosis, calpain, cell invasion, oral squamous cell carcinoma

How to cite this article:
Shome S, Sil S. Calpain and oral cancer – A novel approach to detect cancer cell invasion. Indian J Dent Sci 2022;14:51-2

How to cite this URL:
Shome S, Sil S. Calpain and oral cancer – A novel approach to detect cancer cell invasion. Indian J Dent Sci [serial online] 2022 [cited 2022 Jan 24];14:51-2. Available from: http://www.ijds.in/text.asp?2022/14/1/51/334525

Introduction

Calpains are Ca²⁺-dependent nonlysosomal neutral proteases acting upon various cellular procedures.^[1] This endogenous neutral protease resides within cytosol and mitochondria^[1] promoting a wide spectrum of metabolic activities ranging from cellular apoptosis to cellular invasion in cancer.^[2],[3] This 15-member class of proteases is inhibited by another endogenous protein calpastatin which hinders the basal cellular activity of calpain.^[1] Intracellular cysteine proteases calpains ubiquitously remain as a tissue-specific isoform manner in higher animals.^[4] Namely, calpain 1 and calpain 2 are widely involved in cancer formation, cancer cell migration, and invasion and studies relating to its role in oral squamous cell carcinoma (OSCC) pathogenesis are widely going on.^[1] The well-known fact is that OSCC is a multifactorial disease encompassing genetic and epigenetic factors which accounts for 90% of all the head-and-neck cancers.^[5] The riddle of cancer pathogenesis, locoregional recurrences, distant metastasis, and unresponsiveness to treatment protocol compels the discovery of novel markers, one of which is calpain. The tireless efforts of scientists have evolved to delineate the role of different isoforms of calpain in cellular apoptosis as well as cell motility and invasion. The following article speculates a short review on the role of calpain in cellular apoptosis and cell migration in the context of OSCC.

Morphology of Calpain Molecule

Calpains are widely expressed in various tissues and organs such as endothelial cells, placenta, smooth muscle cells, brain, and skin.^[1] Overactivity in neural tissue leads to neurodegeneration while baseline activity promotes neuroprotectivity.^[6] Its conformation allows it to bind with Ca²⁺ before it becomes metabolically active.^[1] At first the analogous enzyme to this Calpain molecule was discovered, later on the purified form of this analogous enzyme was named as Calpain.^[7] Cloning of genetic sequences has established 15 calpain isoforms in human beings where there are two small regulatory subunits – CAPNS1 and CAPNS2 associated with endogenous inhibitor calpastatin.^[7] The metabolic characteristic of calpain lies in its proteolytic activity in a neutral pH just like in the case of another cysteine protease, i.e., caspase.^[7] The orchestration of calpain proteolysis brings about cell metabolism, signal transduction, and altered cell morphogenesis.^[7] When basal calpain activity is jeopardized or it is overexpressed, anomalies and certain systemic diseases including fetal lethality, muscular dystrophy, neurodegeneration, and development of malignancy are seen reflecting its strict regulation.^[1],[7] As it is distributed in different human tissues and organs, this is also dispersed in a species-specific manner.^[7] The mammalian conventional calpain has μ and m domains which are manifested as heterodimers consisting of regulatory small subunit and one large catalytic subunit.^[7] As the small subunits are heterodimers in nature, they discriminate themselves on the basis of in vitro Ca²⁺ concentration.^[1],[7] Autolytic displacement of the N-terminal α-helix of the catalytic subunit of calpain leads to its activity in lower Ca²⁺ concentration and variable substrate specificity.^[7] cDNA cloning shows both its over and under expression affecting cell survival and apoptosis. The exact mechanism is beyond the scope of discussion here.^[2],[7]

Calpain and Cellular Apoptosis

Programmed cell death or apoptosis is the ultimate fate of a eukaryotic cell which is amplified by various pathologic stimuli.^[2] The narration of the entire span of all the intrinsic and extrinsic mechanisms of apoptosis is beyond the scope of discussion in this short review. The familiarity of Ca²⁺-independent caspase in relation to apoptosis is well known.^[2] Our emphasis is on calpain which promotes degenerative cell response heading toward apoptosis by proteolysis.^[2] The activation of inactive pro-enzyme form of calpain is triggered by increased intracellular Ca²⁺ which is also considered as one of the alluring prerequisites for apoptosis.^[2] Calpain is highly sensitive to Ca²⁺ concentration, hence transient increase in cytosolic free Ca²⁺ promotes the autolysis of propeptide protein giving rise to conformational changes and separation of truncated protein.^[2] Pertaining to OSCC, cellular apoptosis is an antagonistic phenomenon as the neoplastic cells exhibit increased cell survival. The “double-edged sword” calpain is also responsible for cellular invasion and migration in OSCC showing a disparity in its role in apoptosis.

Calpain and Oral Squamous Cell Carcinoma

Two isoforms are named in this article where role of calpain 1 is to help in cancer cell invasion.^[3] In vitro studies on various cell lines and cell cultures were carried out in Japan and the USA where keratinocytes render migratory and invasive properties by Western blot analysis, RNA isolation, and quantitative polymerase chain reaction.^[3] The calpain 1 small interfering RNA (siRNA) sequence has analyzed its role on two crucial cellular events in OSCC, i.e., cell cycle and apoptosis.^[1],[3] Rate of apoptosis was detected through flow cytometry, siRNA sequencing, and fluorescein-labeled annexin V.^[3] The landmark study of MA et al. has advocated that the protein and mRNA expression in calpain 1 was lowered in comparison to expression of siRNA sequencing.^[3] It was concluded finally that overexpression of siRNA of calpain 1 has a positive connotation with cell survival, cell motility, and cell migration in OSCC cell lines in terms of cell cycle progression and abrogation of apoptosis at a certain level. The calpain 1 knockdown cell line demonstrated hindered cell cycle progression where more cells are found to be gathered in G0/G1 phase with simultaneous decrease of cells in S phase.^[3] Thus, calpain 1 has got a definite chance to be a forerunner to give a predictive value of OSCC outcome and prognosis. On the contrary to calpain 1, another isoform calpain 6 downregulation is observed in cancer progression in OSCC while it is overexpressed carcinosarcoma, osteosarcoma, etc., reflecting its sensitivity and specificity to tissues and Ca²⁺ concentration.^[8]

Conclusion

Calpain, a paradigm shift in the arena of molecular pathology behind carcinogenesis and tumor cell progression, is believed to answer the void of cancer pathogenesis in the near future. Researches on its dynamic role in cellular proliferation are still going on. From the comprehensive knowledge of calpain in the progression of head-and-neck cancer, it is expected to be a pathfinder to unveil newer treatment protocol of course with better prognosis.

Acknowledgment

We are grateful to Prof. Dr. R. R. Paul, Head, Research and Development, Oral and Dental Health Sciences, JIS University, and Prof. Dr. Arup Kumar Ghosh, Head, Department of Oral and Maxillofacial Pathology, HIDSAR, for all the academic inputs for publication of this review article.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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